© 2019 Oxford University Press. All rights reserved. Background. Adverse upper limb musculoskeletal effects occur after surgical procedures and radiotherapy for breast cancer and can interfere with activities of daily living. Objective. The objective of this study was to examine the effects of a 16-week exercise intervention on shoulder function in women who are overweight or obese and have breast cancer. Design. This study was a randomized controlled trial. Setting. The study was performed at the Division of Biokinesiology and Physical Therapy at the University of Southern California. Participants. One hundred women with breast cancer were randomly allocated to exercise or usual-care groups. The mean (SD) age of the women was 53.5 (10.4) years, 55% were Hispanic white, and their mean (SD) body mass index was 33.5 (5.5) kg/m2. Intervention. The 16-week exercise intervention consisted of supervised, progressive, moderate to vigorous aerobic and resistance exercise 3 times per week. Measurements. Shoulder active range of motion, isometric muscular strength, and patient-reported outcome measures (including Disabilities of the Arm, Shoulder, and Hand and the Penn Shoulder Scale) were assessed at baseline, after the intervention, and at the 3-month follow-up (exercise group only). Differences in mean changes for outcomes were evaluated using mixed-model repeated-measures analysis. Results. Compared with the usual-care group, the exercise group experienced significant increases in shoulder active range of motion (the mean between-group differences and 95% confidence intervals (CIs) were as follows: shoulder flexion = 36.6 [95% CI = 55.2- 20.7°], external rotation at 0° = 23.4° [95% CI = 31.1-12.5°], and external rotation at 90° = 34.3° [95% CI = 45.9-26.2°]), improved upper extremity isometric strength, and improved Disabilities of the Arm, Shoulder, and Hand and Penn Shoulder Scale scores. Limitations. Limitations include a lack of masking of assessors after the intervention, an attention control group, and statistical robustness (shoulder function was a secondary end point). Conclusions. A 16-week exercise intervention effectively improved shoulder function following breast cancer treatment in women who were overweight or obese, who were ethnically diverse, and who had breast cancer.