To review the outcomes of definitive radiotherapy (RT) alone or combined with chemotherapy (CT) in the treatment of squamous cell carcinoma of the anal canal. Between November 1968 and June 2005, 69 patients were treated with curative intent at the University of Florida. Distribution according to T stage was: T1, 11 (16%); T2, 29 (42%); T3, 21 (30%); and T4, 8 (12%). Distribution according to N stage was: N0, 53 (77%); N1, 3 (4%); N2, 7 (10%); and N3, 6 (9%). RT consisted of external beam RT (EBRT) in 30 patients (43%) and EBRT plus brachytherapy in 39 patients (57%). Thirty-eight patients (55%) received adjuvant CT: mitomycin C and fluorouracil, 21 patients (30%); cisplatin plus fluorouracil, 16 patients (23%); and other, 1 patient (1%). Median follow-up for all patients was 7.9 years (range: 0.1-17.3 years). One patient who was disease-free was lost to follow-up at 129 months. The 5-year local control rates were: T1, 100%; T2, 93%; T3, 70%; T4, 88%; and overall, 86%. The 5-year regional control rates were: N0, 96%; N1 and N2, 89%; N3, 100%; and overall, 96%. The 5-year colostomy-free survival rates were: T1, 82%; T2, 89%; T3, 65%; T4, 38%; and overall, 74%. The 5-year cause-specific and overall survival rates were: stage I, 100% and 64%; stage II, 86% and 70%; stage III, 80% and 76%; and overall, 87% and 71%, respectively. Seven patients (10%) developed Radiation Therapy Oncology Group grade 3 late complications and 4 additional patients (6%) experienced grade 4 late complications. A fatal acute complication occurred in 1 patient (1%). The likelihood of cure and colostomy-free survival after EBRT alone or combined with brachytherapy is relatively high and likely improved by adjuvant CT. The acute toxicity of treatment is significant; the major risk is neutropenia and sepsis. Patients with advanced T4 cancers that result in sphincter dysfunction requiring a pretreatment colostomy will usually have a permanent colostomy.