Background: HAART has reduced mortality in HIV-infected patients; however, the risk of non-AIDS-related events has increased, including cancer. We compared mortality in HIV-infected patients with or without cancer with the general population in Italy. Methods: Eligible patients were recorded in the San Raffaele Infectious Diseases Department database. The ratio of observed deaths to expected all-cause deaths (standardized mortality ratio [SMR]) was standardized for age and gender, and stratified by cancer occurrence or year of HIV infection (≤1998 or >1998). Expected all-cause deaths were obtained from the Istituto Superiore di Sanità (Rome, Italy; 2002 data). Results: Among 6,495 HIV-infected patients, contributing 75,171 person-years, the SMR was 6.0 (95% CI 5.7, 6.4); SMRs decreased as age increased. Mortality rates were significantly higher than the general population for patients with or without cancer (SMR=15.1 [95% CI 13.6, 16.7] and 4.8 [95% CI 4.5, 5.1], respectively). For patients with or without cancer, SMRs were higher in those aged <45 years than older patients. SMRs for patients with cancer were almost stable in those infected with HIV ≤1998 (15.3; 95% CI 13.7, 17.0) or >1998 (13.5; 95% CI 9.2, 19.1). Among patients with cancer diagnosed with HIV >1998, age-adjusted SMRs ranged from 216.0 (95% CI 43.4, 631.3) to 6.8 (95% CI 4.7, 9.7) in patients <30 years or ≥70 years, respectively. Conclusions: Mortality in HIV-infected patients remains higher than the general population in Italy, with marked differences according to age, and cancer contributing to an increased excess of mortality.