A Healthy People 2020 objective is to increase the prevalence of healthy-weight adults in the U.S. A systematic review of the effectiveness and safety of strategies to prevent weight gain in adults was performed. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and ClinicalTrials.gov were searched through June 2012. Two reviewers independently reviewed titles, abstracts, and articles. Trials and observational studies with at least 1 year of follow-up that reported on strategies to prevent weight gain or maintain weight were included. Data were abstracted on weight, adherence, safety, and quality-of-life outcomes. The quantity, quality, and consistency of the evidence were graded, with a focus on studies' risks of bias, consistency of results across studies, how directly the question of interest was addressed, and precision of results. A meaningful difference and a significant threshold (p