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To evaluate the incidence rates of anal cancer over the HIV epidemic and assess the impact of HAART use on anal cancer events.We evaluated the incidence of and factors associated with anal cancer using longitudinal data from the prospective U.S. Military Natural History Study (1985–2008). Poisson regression and Cox proportional hazard models were utilized.Among 4506 HIV-infected men with 37 806 person-years of follow-up, anal cancer rates (per 100 000 person-years) increased five-fold, from 11 in the pre-HAART to 55 in the HAART era (P = 0.02). Rates continued to increase, reaching 128 in 2006–2008. Persons with HIV infection for more than 15 years had a 12-fold higher rate than those with less than 5 years (348 vs. 28, P < 0.01). At cancer diagnosis (n = 19), median age was 42 years, median CD4 cell count was 432 cells/μl, 74% had a CD4 nadir cell count less than 200 cells/μl, 42% had a prior AIDS event, and 74% had received HAART. From separate models, prior AIDS event (hazard ratio 3.88, P = 0.01) and lower CD4 nadir (hazard ratio 0.85 per 50 cell, P = 0.03) were associated with anal cancer, with a trend for a history of gonorrhea (hazard ratio 2.43, P = 0.07). Duration of HAART use was not associated with a reduced risk of anal cancer (hazard ratio 0.94, P = 0.42).Incidence rates of anal cancer have progressively increased during the HIV epidemic. Persons with a longer duration of HIV infection have a substantially higher rate of anal cancer. As HIV-infected persons are experiencing longer life expectancies and HAART does not appear protective of anal cancer, studies on preventive strategies are needed.