The aim of the study was to see if topical aloe vera gel would be beneficial in reducing the identified skin side-effects of radiation therapy, including erythema, pain, itching, dry desquamation, and moist desquamation, when compared with aqueous cream. The secondary aim was to assess the effect of other factors known to predict severity of radiation skin reaction, ie, breast size, smoking habit, and one or more drainages of lymphocele after surgery, on other skin side effects. A Phase III study was conducted involving 225 patients with breast cancer after lumpectomy or partial mastectomy, who required a course of radiation therapy using tangential fields. Patients were randomized to either topical aloe vera gel or topical aqueous cream to be applied 3 times per day throughout and for 2 weeks after completion of radiation treatment. Weekly skin assessments were performed by nursing staff. Aqueous cream was significantly better than aloe vera gel in reducing dry desquamation and pain related to treatment. Subjects with D cup or larger size breasts experienced significantly more erythema, regardless of treatment arm. For subjects who had undergone lymphocele drainage, the aloe vera group experienced significantly more pain than the aqueous cream group. Within the aqueous cream arm, smokers were significantly more likely to experience itching within the treatment field than were nonsmokers. Within the aloe vera arm, subjects who had undergone one or more lymphocele drainages after surgery were significantly more likely to experience erythema and itching within the treatment field than those who did not have drainage. In this study, aloe vera gel did not significantly reduce radiation-induced skin side effects. Aqueous cream was useful in reducing dry desquamation and pain related to radiation therapy.