It has been proposed that aloe cream could reduce the severity of skin toxicity from radiation therapy for breast cancer. The present 3-arm study compared control powder with double-blind aloe or placebo cream and found that the patients who had used dry powder skin care during radiation therapy had a lower severity of skin toxicity than that of the patients who had used either the placebo or aloe cream. We recommend a dry powder regimen during radiation therapy to reduce the severity of skin toxicity. Background: The efficacy of aloe extract in reducing radiation-induced skin injury is controversial. The purpose of the present 3-arm randomized trial was to test the efficacy of quality-tested aloe extract in reducing the severity of radiation-induced skin injury and, secondarily, to examine the effect of a moist cream versus a dry powder skin care regimen. Materials and Methods: A total of 248 patients with breast cancer were randomized to powder, aloe cream, or placebo cream. Acute skin toxicity was scored weekly and after treatment at weeks 1, 2, and 4 using a modified 10-point Catterall scale. The patients scored their symptom severity using a 6-point Likert scale and kept an acute phase diary. Results: The aloe formulation did not reduce acute skin toxicity or symptom severity. Patients with a greater body mass index were more likely to develop acute skin toxicity. A similar pattern of increased skin reaction toxicity occurred with both study creams compared with the dry powder regimen. Conclusion: No evidence was found to support prophylactic application of quality aloe extract or cream to improve the symptoms or reduce the skin reaction severity. Our results support a dry skin care regimen of powder during radiation therapy.