IMPORTANCE To our knowledge, no randomized clinical trials have assessed the effects of the combination of weight loss and home-based exercise programs on lymphedema outcomes. OBJECTIVE To assess weight loss, home-based exercise, and the combination of weight loss and home-based exercise with clinical lymphedema outcomes among overweight breast cancer survivors. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial (Women in Steady Exercise Research [WISER] Survivor clinical trial ) of 351 overweight breast cancer survivors with breast cancer-related lymphedema (BCRL) was conducted in conference rooms at academic and community hospitals and in the homes of participants from March 12, 2012, to May 28, 2016; follow-up was conducted for 1 year from the start of the intervention. Statistical analysis by intention to treat was performed from September 26, 2018, to October 28, 2018. INTERVENTIONS A 52-week, home-based exercise program of strength/resistance training twice per week and 180 minutes of walking per week, a weight loss program of 20 weeks of meal replacements and 52 weeks of lifestyle modification counseling, and a combination of the home-based exercise and weight loss programs. MAIN OUTCOMES AND MEASURES The 12-month change in the percentage of interlimb volume difference.RESULTS Of 351 participants, 90 were randomized to the control group (facility-based lymphedema care with no home-based exercise or weight loss intervention), 87 to the exercise intervention group, 87 to the weight loss intervention group, and 87 to the combined exercise and weight loss intervention group; 218 (62.1%) were white, 122 (34.8%) were black, and 11 (3.1%) were of other races or ethnicities. Median time since breast cancer diagnosis was 6 years (range, 1-29 years). Mean (SD) total upper extremity score changes from the objective clinical evaluation were −1.40 (11.10) in the control group, −2.54 (13.20) in the exercise group, −3.54 (12.88) in the weight loss group, and −3.84 (10.09) in the combined group. Mean (SD) overall upper extremity score changes from the self-report survey were −0.39 (2.33) in the control group, −0.12 (2.14) in the exercise group, −0.57 (2.47) in the weight loss group, and −0.62 (2.38) in the combined group. Weight loss from baseline was −0.55% (95% CI, −2.22% to 1.11%) in the control group, −8.06% (95% CI, −9.82% to 6.29%) in the combined group, −7.37% (95% CI, −8.90% to −5.84%) in the weight loss group, and −0.44% (95% CI, −1.81% to 0.93%) in the exercise group. CONCLUSIONS AND RELEVANCE Study results indicate that weight loss, home-based exercise, and combined interventions did not improve BCRL outcomes; a supervised facility-based program of exercise may be more beneficial than a home-based program for improving lymphedema outcomes. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01515124