BACKGROUND: Severe acute malnutrition affects 13 million children worldwide and causes 1-2 million deaths every year. Our aim was to assess the clinical and nutritional efficacy of a probiotic and prebiotic functional food for the treatment of severe acute malnutrition in a HIV-prevalent setting. METHODS: We recruited 795 Malawian children (age range 5 to 168 months [median 22, IQR 15 to 32]) from July 12, 2006, to March 7, 2007, into a double-blind, randomised, placebo-controlled efficacy trial. For generalisability, all admissions for severe acute malnutrition treatment were eligible for recruitment. After stabilisation with milk feeds, children were randomly assigned to ready-to-use therapeutic food either with (n=399) or without (n=396) Synbiotic2000 Forte. Average prescribed Synbiotic dose was 10(10) colony-forming units or more of lactic acid bacteria per day for the duration of treatment (median 33 days). Primary outcome was nutritional cure (weight-for-height >80% of National Center for Health Statistics median on two consecutive outpatient visits). Secondary outcomes included death, weight gain, time to cure, and prevalence of clinical symptoms (diarrhoea, fever, and respiratory problems). Analysis was on an intention-to-treat basis. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN19364765. FINDINGS: Nutritional cure was similar in both Synbiotic and control groups (53.9% [215 of 399] and 51.3% [203 of 396]; p=0.40). Secondary outcomes were also similar between groups. HIV seropositivity was associated with worse outcomes overall, but did not modify or confound the negative results. Subgroup analyses showed possible trends towards reduced outpatient mortality in the Synbiotic group (p=0.06). INTERPRETATION: In Malawi, Synbiotic2000 Forte did not improve severe acute malnutrition outcomes. The observation of reduced outpatient mortality might be caused by bias, confounding, or chance, but is biologically plausible, has potential for public health impact, and should be explored in future studies. FUNDING: Department for International Development (DfID).