Management of patients with squamous cell carcinoma of the anus (SCCA) has remained virtually unchanged since the 1980s. By contrast, the demographics of SCCA are evolving, with the emergence of a high-risk group of patients: HIV-positive male homosexuals are prone to develop anal intra-epithelial neoplasia and rapidly progress towards invasive SCCA. By many aspects, anal cancer is similar to uterine cervix cancer - a sexually transmitted disease driven by oncogenic human papillomavirus (HPV) infection. Thus, for many patients, SCCA results from the combination of two preventable diseases, HPV and HIV infection. This article reviews current evidence suggesting that a new, more preventive approach is needed in order to improve the clinical outcome of SCCA in HIV-positive patients.