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To systematically review and describe currently available approaches to supporting maintenance of weight loss in obese adults and to assess the evidence for the effectiveness of these interventions.Systematic review with meta-analysis.Medline, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials.Studies were identified through to January 2014. Randomised trials of interventions to maintain weight loss provided to initially obese adults (aged ≥18) after weight loss of ≥5% body weight with long term (≥12 months) follow-up of weight change (main outcome) were included.Potential studies were screened independently and in duplicate; study characteristics and outcomes were extracted. Meta-analyses were conducted to estimate the effects of interventions on weight loss maintenance with the inverse variance method and a random effects model. Results are presented as mean differences in weight change, with 95% confidence intervals.45 trials involving 7788 individuals were included. Behavioural interventions focusing on both food intake and physical activity resulted in an average difference of -1.56 kg (95% confidence interval -2.27 to -0.86 kg; 25 comparisons, 2949 participants) in weight regain compared with controls at 12 months. Orlistat combined with behavioural interventions resulted in a -1.80 kg (-2.54 to -1.06; eight comparisons, 1738 participants) difference compared with placebo at 12 months. All orlistat studies reported higher frequencies of adverse gastrointestinal events in the experimental compared with placebo control groups. A dose-response relation for orlistat treatment was found, with 120 mg doses three times a day leading to greater weight loss maintenance (-2.34 kg, -3.03 to -1.65) compared with 60 mg and 30 mg three times a day (-0.70 kg, 95% confidence interval -1.92 to 0.52), P=0.02.Behavioural interventions that deal with both diet and physical activity show small but significant benefits on weight loss maintenance.