Copyright 2016 American Medical Association. All rights reserved. IMPORTANCE Weight gain occurs commonly in young adults and has adverse effects on health. OBJECTIVE To compare 2 self-regulation interventions vs control in reducing weight gain in young adults over a mean follow-up of 3 years. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial in 2 academic settings of 599 participants aged 18 to 35 years with body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 21.0 to 30.0, recruited via mailings and emails from August 2010 to February 2012. Data were analyzed from January 2015 to January 2016. INTERVENTIONS Participants were randomized to control, self-regulation plus small changes, or self-regulation plus large changes. Both interventions focused on frequent self-weighing to cue behavior changes. "Small changes" taught participants to reduce intake and increase activity, both by approximately 100 calories per day. "Large changes" focused on losing 2.3 to 4.5 kg initially to buffer against expected weight gain. MAIN OUTCOMES AND MEASURES Changes inweight from baseline over mean follow-up of 3 years. Secondary outcomes included proportion gaining at least 0.45 kg from baseline, proportion developing obesity (BMI,30.0), and weight change baseline to 2 years. RESULTS Among the 599 participants (22%men; 27%minority; mean [SD] age, 27.7 [4.4] years; mean [SD] BMI, 25.4 [2.6]), mean (SE) weight changes over a mean follow-up of 3 years were 0.26 (0.22), -0.56 (0.22), and -2.37 (0.22) kg in the control, small-changes, and large-changes groups, respectively (P < .001). Differences among all 3 groups were significant (large changes vs control, P < .001; small changes vs control, P = .02; large changes vs small changes, P < .001). On secondary outcomes, both interventions significantly reduced incidence of obesity relative to control (mean [SE], 8.6%[2.0%], 7.9% [2.0%], and 16.9% [2.7%] in the large-changes, small-changes, and control groups, respectively; P = .02 for large changes vs control and P = .002 for small changes vs control); a smaller percentage of participants in the large-changes group gained 0.45 kg or more (mean [SE], 23.6%[2.8%], 32.5%[3.8%], and 40.8%[4.4%], respectively; P < .001 vs control and P = .02 vs small changes) and weight change from baseline to 2 years was greater in control than in small or large changes (mean [SE], 0.54 [0.33], -0.77 [0.33], and -1.50 [0.34] kg, respectively; P = .02 vs small changes and P < .001 vs large changes). CONCLUSIONS AND RELEVANCE Self-regulation with large or small changes both reduced weight gain in young adults over 3 years relative to control, but the large-changes intervention was more effective.