Severe acute malnutrition affects 13 million children worldwide and causes 1–2 million deaths every year. This study assessed the clinical and nutritional efficacy of a probiotic and prebiotic functional food for the treatment of severe acute malnutrition in an HIV-prevalent setting. Researchers recruited 795 Malawian children (age range 5 to 168 months [median 22, IQR 15–32]) from 12 July 2006 to 7 March 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 or withoutSynbiotic2000 Forte. Primary outcome was nutritional cure (weight-for-height >80 per cent 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. Nutritional cure was similar in both Synbiotic and control groups. 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. 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.