Purpose: Squamous cell carcinoma of the anus (SCCA) has been routinely treated with chemotherapy and radiation (CR). Prior to the era of highly active anti-retroviral therapy (HAART) for treatment of human immunodeficiency virus infection (HIV), HIV patients faired poorly with CR. There is a paucity of data on the outcome of HIV patients treated with CR in the HAART era. We outline our experience. Methods: Retrospective review of prospective database of all HIV patients with SCCA treated at a tertiary care center from 1999 to 2005. Age, sex, CD4 count, viral load, treatment toxicity, survival and surgical intervention were recorded. Survival was calculated with Kaplan-Meier method, and Students-t was utilized as appropriate. Results: 15 patients were identified, 12 males. Mean age 43 (34-51). 13/15 were compliant with HAART. All patients received CR with mitomycin-C and 5-fluorouracil. Radiation dose ranged from 54Gy to 68Gy. 14/15 completed CR with 1 death at induction from neutropenic sepsis. Initial complete response was seen in 12/15(80%). 1 recurred and underwent abdominal perineal resection, 1 had recurrent in situ carcinoma, 1 had a partial response with unresectable disease, 1 declined follow-up exam. At mean follow-up of 26 months (1-48), 4 deaths occurred. Overall survival at 1, 2, and 3 years was 93.3%, 75.4%, and 56.6%. No difference in mean CD4 or viral loads was identified between survivors and non-survivors. Need for surgical intervention was significant, with 6/15 (40%) requiring laparotomy and 4/15 (27%) requiring permanent stoma either for recurrent/persistent disease or radiation stenosis. Conclusions: CR for SCCA in the HAART era is initially well tolerated with 75% survival at 2 years. However, laparotomy (40%) and permanent diversion (27%) are frequently necessary, emphasizing the need for active involvement of the surgeon in a multidisciplinary team. Future studies with longer follow-up comparing outcomes to a matched non-HIV population are warranted.