CONTEXT: Multiple risk behaviors are common and associated with developing chronic conditions such as heart disease, cancer, or Type 2 diabetes. A systematic review, meta-analysis, and meta-regression of the effectiveness of multiple risk behavior interventions was conducted. EVIDENCE ACQUISITION: Six electronic databases including MEDLINE, EMBASE, and PsycINFO were searched to August 2016. RCTs of non-pharmacologic interventions in general adult populations were selected. Studies targeting specific at-risk groups (such as people screened for cardiovascular risk factors or obesity) were excluded. Studies were screened independently. Study characteristics and outcomes were extracted and risk of bias assessed by one researcher and checked by another. The Behaviour Change Wheel and Oxford Implementation Index were used to code intervention content and context. EVIDENCE SYNTHESIS: Random-effects meta-analyses were conducted. Sixty-nine trials involving 73,873 individuals were included. Interventions mainly comprised education and skills training and were associated with modest improvements in most risk behaviors: increased fruit and vegetable intake (0.31 portions, 95% CI=0.17, 0.45) and physical activity (standardized mean difference, 0.25; 95% CI=0.13, 0.38), and reduced fat intake (standardized mean difference, -0.24; 95% CI=-0.36, -0.12). Although reductions in smoking were found (OR=0.78, 95% CI=0.68, 0.90), they appeared to be negatively associated with improvement in other behaviors (such as diet and physical activity). Preliminary evidence suggests that sequentially changing smoking alongside other risk behaviors was more effective than simultaneous change. But most studies assessed simultaneous rather than sequential change in risk behaviors; therefore, comparisons are sparse. Follow-up period and intervention characteristics impacted effectiveness for some outcomes. CONCLUSIONS: Interventions comprising education (e.g., providing information about behaviors associated with health risks) and skills training (e.g., teaching skills that equip participants to engage in less risky behavior) and targeting multiple risk behaviors concurrently are associated with small changes in diet and physical activity. Although on average smoking was reduced, it appeared changes in smoking were negatively associated with changes in other behaviors, suggesting it may not be optimal to target smoking simultaneously with other risk behaviors.