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The incidence of non-AIDS-defining malignancies (non-ADMs) is reported as unchanged or increasing in the highly active antiretroviral therapy era. Whether incidence of non-ADM is significantly higher in HIV-infected than in HIV-uninfected patients remains unclear.Incidence rates of malignancies were calculated in a cohort of veterans in care for HIV-infected and age, race, and gender-matched uninfected patients from 1997 to 2004. For HIV-infected patients, CD4 counts closest to first observation date were compared between those with and without cancer.Thirty three thousand four hundred twenty HIV-infected and 66,840 HIV-uninfected patients were followed for a median of 5.1 and 6.4 years. The incidence rate ratio of HIV infected to HIV uninfected was 1.6 (1260 vs. 841 per 100,000 person-years; 95% confidence interval: 1.5 to 1.7). Incidence rate ratio for individual cancers was highest for anal cancer (14.9; confidence interval: 10.1 to 22.1). Among HIV-infected patients, median CD4 counts were lower for those with non-ADM (249 vs. 270, P = 0.02), anal cancer (156 vs. 270; P < 0.001), and Hodgkin lymphoma (217 vs. 269; P = 0.03). Prostate cancer was associated with a higher CD4 count (311 vs. 266; P < 0.001).In the highly active antiretroviral therapy era, the incidence of non-ADMs is higher among HIV-infected than HIV-uninfected patients, adjusting for age, race, and gender. Some non-ADMs do not seem to be associated with significantly lower CD4 counts.