Background: Inconsistent evidence about product effectiveness to prevent moist desquamation during radiation treatment and minimal research about the acceptability to patients of recommended products prompted this study. Objective: This randomized controlled trial compared the effectiveness of 2 creams at minimizing the incidence of moist desquamation in a tropical setting and explored which product was most acceptable to patients receiving radiation treatment. Methods: Participants (n = 255) were stratified according to breast or chest wall radiation treatment and randomly allocated to use a moisturizing or barrier cream. Nurses assessed radiation skin reactions weekly with a standardized grading system, and patients were telephoned 1 month after completing treatment for a final skin assessment. Participants completed an Acceptability Survey at similar times. Results: At treatment completion, 15% of participants had moist desquamation. An additional 26% self-reported this at follow-up. Risk factors for moist desquamation included increased breast cup size and body mass index. The barrier cream significantly reduced the incidence of moist desquamation during treatment in patients receiving radiation to the chest wall ((2) = 3.93, P = .047). Participants preferred the barrier cream over the moisturizer ((2) = 5.81, P = .02) during treatment. Conclusions: This study identified a relatively high incidence of moist desquamation in patients receiving radiation therapy for breast cancer. Future patients will have information about product effectiveness in minimizing moist desquamation when choosing skin care products. Implications for Practice: Structured discharge planning and patient education need to include information about factors that contribute to the likelihood of developing moist desquamation.