BACKGROUND: Engagement in multiple risk behaviours can have adverse consequences for health during childhood, during adolescence, and later in life, yet little is known about the impact of different types of interventions that target multiple risk behaviours in children and young people, or the differential impact of universal versus targeted approaches. Findings from systematic reviews have been mixed, and effects of these interventions have not been quantitatively estimated. OBJECTIVES: To examine the effects of interventions implemented up to 18 years of age for the primary or secondary prevention of multiple risk behaviours among young people. SEARCH METHODS: We searched 11 databases (Australian Education Index; British Education Index; Campbell Library; Cumulative Index to Nursing and Allied Health Literature (CINAHL); Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; Embase; Education Resource Information Center (ERIC); International Bibliography of the Social Sciences; MEDLINE; PsycINFO; and Sociological Abstracts) on three occasions (2012, 2015, and 14 November 2016)). We conducted handsearches of reference lists, contacted experts in the field, conducted citation searches, and searched websites of relevant organisations. SELECTION CRITERIA: We included randomised controlled trials (RCTs), including cluster RCTs, which aimed to address at least two risk behaviours. Participants were children and young people up to 18 years of age and/or parents, guardians, or carers, as long as the intervention aimed to address involvement in multiple risk behaviours among children and young people up to 18 years of age. However, studies could include outcome data on children > 18 years of age at the time of follow-up. Specifically,we included studies with outcomes collected from those eight to 25 years of age. Further, we included only studies with a combined intervention and follow-up period of six months or longer. We excluded interventions aimed at individuals with clinically diagnosed disorders along with clinical interventions. We categorised interventions according to whether they were conducted at the individual level; the family level; or the school level. DATA COLLECTION AND ANALYSIS: We identified a total of 34,680 titles, screened 27,691 articles and assessed 424 full-text articles for eligibility. Two or more review authors independently assessed studies for inclusion in the review, extracted data, and assessed risk of bias.We pooled data in meta-analyses using a random-effects (DerSimonian and Laird) model in RevMan 5.3. For each outcome, we included subgroups related to study type (individual, family, or school level, and universal or targeted approach) and examined effectiveness at up to 12 months' follow-up and over the longer term (> 12 months). We assessed the quality and certainty of evidence using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included in the review a total of 70 eligible studies, of which a substantial proportion were universal school-based studies (n = 28; 40%). Most studies were conducted in the USA (n = 55; 79%). On average, studies aimed to prevent four of the primary behaviours. Behaviours that were most frequently addressed included alcohol use (n = 55), drug use (n = 53), and/or antisocial behaviour (n = 53), followed by tobacco use (n = 42). No studies aimed to prevent self-harm or gambling alongside other behaviours.Evidence suggests that for multiple risk behaviours, universal school-based interventions were beneficial in relation to tobacco use (odds ratio (OR) 0.77, 95% confidence interval (CI) 0.60 to 0.97; n = 9 studies; 15,354 participants) and alcohol use (OR 0.72, 95% CI 0.56 to 0.92; n = 8 studies; 8751 participants; both moderate-quality evidence) compared to a comparator, and that such interventions may be effective in preventing illicit drug use (OR 0.74, 95% CI 0.55 to 1.00; n = 5 studies; 11,058 participants; low-quality evidence) and engagement in any antisocial behaviour (OR 0.81, 95% CI 0.66 to 0.98; n = 13 studies; 20,756 participants; very low-quality evidence) at up to 12 months' follow-up, although there was evidence of moderate to substantial heterogeneity (I² = 49% to 69%). Moderate-quality evidence also showed that multiple risk behaviour universal school-based interventions improved the odds of physical activity (OR 1.32, 95% CI 1.16 to 1.50; I² = 0%; n = 4 studies; 6441 participants). We considered observed effects to be of public health importance when applied at the population level. Evidence was less certain for the effects of such multiple risk behaviour interventions for cannabis use (OR 0.79, 95% CI 0.62 to 1.01; P = 0.06; n = 5 studies; 4140 participants; I² = 0%; moderate-quality evidence), sexual risk behaviours (OR 0.83, 95% CI 0.61 to 1.12; P = 0.22; n = 6 studies; 12,633 participants; I² = 77%; low-quality evidence), and unhealthy diet (OR 0.82, 95% CI 0.64 to 1.06; P = 0.13; n = 3 studies; 6441 participants; I² = 49%; moderate-quality evidence). It is important to note that some evidence supported the positive effects of universal school-level interventions on three or more risk behaviours.For most outcomes of individual- and family-level targeted and universal interventions, moderate- or low-quality evidence suggests little or no effect, although caution is warranted in interpretation because few of these studies were available for comparison (n ≤ 4 studies for each outcome).Seven studies reported adverse effects, which involved evidence suggestive of increased involvement in a risk behaviour among participants receiving the intervention compared to participants given control interventions.We judged the quality of evidence to be moderate or low for most outcomes, primarily owing to concerns around selection, performance, and detection bias and heterogeneity between studies. AUTHORS' CONCLUSIONS: Available evidence is strongest for universal school-based interventions that target multiple- risk behaviours, demonstrating that they may be effective in preventing engagement in tobacco use, alcohol use, illicit drug use, and antisocial behaviour, and in improving physical activity among young people, but not in preventing other risk behaviours. Results of this review do not provide strong evidence of benefit for family- or individual-level interventions across the risk behaviours studied. However, poor reporting and concerns around the quality of evidence highlight the need for high-quality multiple- risk behaviour intervention studies to further strengthen the evidence base in this field.