Importance: Women with large breast size treated with adjuvant breast radiotherapy (RT) have a high rate of acute toxic effects of the skin. Breast RT in the prone position is one strategy that may decrease these toxic effects. Objective: To determine if breast RT in the prone position reduces acute toxic effects of the skin when compared with treatment in the supine position. Design, Setting, and Participants: This phase 3, multicenter, single-blind randomized clinical trial accrued patients from 5 centers across Canada from April 2013 to March 2018 to compare acute toxic effects of breast RT for women with large breast size (bra band ≥40 in and/or ≥D cup) in the prone vs supine positions. A total of 378 patients were referred for adjuvant RT and underwent randomization. Seven patients randomized to supine position were excluded (5 declined treatment and 2 withdrew consent), and 14 patients randomized to prone position were excluded (4 declined treatment, 3 had unacceptable cardiac dose, and 7 were unable to tolerate being prone). Data were analyzed from April 2019 through September 2020. Interventions: Patients were randomized to RT in the supine or prone position. From April 2013 until June 2016, all patients (n = 167) received 50 Gy in 25 fractions (extended fractionation) with or without boost (range, 10-16 Gy). After trial amendment in June 2016, the majority of patients (177 of 190 [93.2%]) received the hypofractionation regimen of 42.5 Gy in 16 fractions. Main Outcomes and Measures: Main outcome was moist desquamation (desquamation). Results: Of the 357 women (mean [SD] age, 61 [9.9] years) included in the analysis, 182 (51.0%) were treated in the supine position and 175 (49.0%) in prone. There was statistically significantly more desquamation in patients treated in the supine position compared with prone (72 of 182 [39.6%] patients vs 47 of 175 [26.9%] patients; OR, 1.78; 95% CI, 1.24-2.56; P = .002), which was confirmed on multivariable analysis (OR, 1.99; 95% CI, 1.48-2.66; P < .001), along with other independent factors: use of boost (OR, 2.71; 95% CI, 1.95-3.77; P < .001), extended fractionation (OR, 2.85; 95% CI, 1.41-5.79; P = .004), and bra size (OR, 2.56; 95% CI, 1.50-4.37; P < .001). Conclusions and Relevance: This randomized clinical trial confirms that treatment in the prone position decreases desquamation in women with large breast size receiving adjuvant RT. It also shows increased toxic effects using an RT boost and conventional fractionation. Trial Registration: ClinicalTrials.gov Identifier: NCT01815476.