Clinical trials of obesity treatments have been limited by substantial dropout. Participant-level variables do not reliably predict attrition, and study-level variables have not yet been examined. We searched MEDLINE and identified 24 large randomized controlled trials of weight loss medications. These trials were comprised of 23 placebo and 32 drug groups. Two authors independently extracted the following for each treatment group: (i) treatment received; (ii) design characteristics (inclusion of a lead-in period, selection of participants with weight-related comorbidities, study location and number of study visits); (iii) sample characteristics (sample size, % female, and mean baseline age and body mass index); and (iv) attrition (total, adverse event [AE]-related and non-AE-related) at 1 year. The primary outcome was total attrition, which was significantly related to treatment (i.e. 34.9%, 28.6%, 28.3% and 35.1% in placebo, orlistat, sibutramine and rimonabant groups, respectively, P < 0.0001). In adjusted multivariable models, total attrition was significantly lower in groups that completed a pre-randomization lead-in period than in those that did not (29.1% vs. 39.9%, P < 0.01). Gender also was significantly related to total attrition; groups with more women had higher dropout (P < 0.01). The pattern was similar for predicting non-AE-related attrition. Findings suggest ways to design studies that maximize retention.