It has been reported that arsenic trioxide (As2O3) is an apoptosis inducer and radiation sensitizer for various cancer cell lines. In this study of breast cancer patients, we examined the combined effect of topical As2O3 and radiation therapy on fungating and/or skin-infiltrating lesions of breast cancer. The dermatological, gastrointestinal, hematological, renal and hepatic toxicities of the treatment were also monitored. As2O3 gel (0.05%) was applied to tumor lesions 1 h prior to delivery of each fraction, with the gel removed about 5 min before the irradiation. Superficial radiation was delivered using an electron beam from a linear accelerator. Every week, the tumor lesions were photographed to evaluate effectiveness, and blood was sampled to monitor changes in hemogram and biochemical profile. Seven breast cancer patients with cutaneous metastasis were enrolled in this study. In terms of tumor, the rates for complete, partial response and stable disease were 42.9 (three of seven), 42.9 (three of seven) and 14.3% (one of seven), respectively. The skin pain, assessed by a visual analog scale, and secretion from all of the seven superficial and fungating wounds decreased markedly after treatment. Significant bone marrow suppression or granulocytosis was not noted. Further, changes in renal and hepatic function were also not significant. It seems reasonable to conclude that As2O3 may be an effective and safe radiosensitizer for palliative radiotherapy for skin-infiltrating lesions of breast cancer.