Chemoradiation therapy for anal cancer was carried out in 58 patients using low-dose, continuous infusion of 5-fluorouracil (5-FU) with or without continuous infusion of cisplatin (cDDP) and external beam irradiation (chemoXRT). Thirty-nine patients received 5-FU chemoXRT resulting in a local control rate of 50% in those receiving a total dose of < 45 Gy, 73% for those receiving 50-54 Gy, and 83% for those receiving > 60 Gy. The actuarial local control rate at 2 years was 77% after chemoXRT alone; overall local control was 67% at 5 years. In 18 patients receiving 5-FU plus cisplatin with radiation doses of 54-55 Gy, actuarial local control was 85% at 2 years. Fifteen patients failed chemoXRT, 13 of whom had abdominoperineal resection for salvage; the overall local control rate was 93% (54/58). The actuarial survival at 5 years was 81% for the 5-FU chemoXRT group and 94% at 2 years for the 5-FU plus cisplatin chemoXRT group; median follow-up was 54 and 20 months, respectively. Diarrhea and nausea were the most frequent early reactions and were ameliorated by limiting the duration of chemotherapy to 5 days/week and by using XRT techniques to exclude the small bowel from the radiation portal. Serious late radiation complications have not been observed and may be related to XRT fractionation and the use of protracted chemotherapy infusion. The absence of late morbidity coupled with the high local control rate by the use of this chemoXRT program is an area to investigate for improving the therapeutic ratio for the treatment of anal cancers.