Squamous cell carcinoma of the anal canal (SCCA) is etiologically linked to human papillomavirus, and its incidence is increased among the immunosuppressed. We used data from the Surveillance, Epidemiology, and End Results program to analyze the incidence of SCCA in relation to 3 separate periods during the HIV epidemic: the pre-HIV era (1973-1981), the HIV era (1982-1995), and the highly active antiretroviral treatment (HAART) era (1996-2001). The incidence per 100,000 population of SCCA increased from 0.6 in the pre-HIV era to 0.8 in the HIV era and to 1.0 in the HAART era. The gap in SCCA incidence between women and men decreased from a ratio of 1.6:1 in the pre-HIV era to 1.5:1 in the HIV era and to 1.2:1 in the HAART era. There was a significant increase in incidence rates among men and women aged 30 to 54 years in the HAART era compared with the HIV era. Men were more likely to be diagnosed with early-stage disease, but they were less likely than women to receive radiation therapy. The incidence of SCCA has particularly increased among men and those between 30 and 54 years of age since the introduction of HAART.