Purpose/Objective: There is an increased risk of anal squamous cell carcinoma in patients affected with HIV/AIDS, often occurring within perianal condylomata. Prior to the era of effective anti-retroviral therapy, HIV/AIDS patients with secondary malignancies including anal carcinomas experienced significant life threatening bone marrow and skin/mucosal normal tissue toxicities with the use of chemotherapy and/or radiation therapy. The purpose of this study is to compare treatment outcomes in HIV/AIDS+ versus HIV− patients with anal squamous cell carcinomas treated with standard combined modality therapy in the era of effective retroviral therapy. Materials/Methods: A total of 32 sequential patients including 14 HIV+ (12 males, 2 females) (5 with AIDS) and 18 HIV− (5 males, 13 females) patients were diagnosed with invasive anal squamous cell carcinoma at University Hospitals of Cleveland from 1998-2004. All patients underwent standard staging studies at diagnosis including CT scans of the chest, abdomen and pelvis with contrast and routine blood and serum chemistry testing, as well as pretreatment HIV viral loads and immunology studies in HIV+ patients. Patients were prospectively staged using AJCC, 6th edition criteria (2002). Patients received 3-D conformal radiation to a total dose of 50.4–54 Gy for early stage disease and 59.4–68.4 for advanced disease with either 5-FU/Mitomycin-C or 5-FU/Cisplatinum at standard doses during weeks 1 and 5 of radiation. Acute (during treatment), subacute (<6 months following treatment) and late (>6 months following treatment) toxicities were recorded using NCI Common Toxicity Criteria, Version 3.0. Clinical tumor responses by physical exam, repeat anoscopy and CT scans were performed every 3–4 months for the first year and every 4–6 months for years 2–5 or until disease recurrence. Suspicious skin/mucosal abnormalities were biopsied during follow-up. Results: HIV+ patients (median age at diagnosis: 45; range from 34–51) were diagnosed with invasive anal squamous cell carcinoma an average of 17 years younger than HIV− patients (median age at diagnosis: 60; range from 37–81). A majority of both groups presented with an early stage disease (Stage I/II; 11 HIV+ and 12 HIV−) while 3 HIV+ patients and 5 HIV− patients had stage III A or B disease. One patient (HIV−) had stage IV disease. The clinical/pathological complete response rate was similar in HIV+ (12/14, 86%) and HIV− (16/18, 89%) groups. With a median follow-up of 28 months (8-66 months), 11/14 (79%) HIV+ and 15/18 (83%) HIV− patients remain disease-free. Surgical salvage was not effective in 1 HIV+ and 2 HIV− patients with a partial response following combined modality therapy. Two patients (1 HIV+, 1 HIV−) achieving a complete local response died of metastatic disease. Significant acute toxicities including myelosuppression (1 HIV+, Grade 3), perineal skin toxicity requiring radiation treatment breaks for >1 week (1 HIV+), and fever/neutropenia hospital admissions (1 HIV−) were uncommon. Subacute and late toxicities including persistent rectal pain requiring narcotic analgesics, rectal bleeding, rectal incontinence, and chronic diarrhea requiring medications were also uncommon and did not vary by HIV status. One HIV+ required surgery for a partial bowel obstruction without cancer and one HIV− patient required a colostomy for chronic rectal incontinence and pain without cancer. Conclusions: In the era of effective anti-retroviral therapy, HIV+ patients with invasive squamous cell carcinoma can be effectively treated with standard combined modality therapy with acceptable acute and subacute/late toxicities.