Background: Non-AIDS non-HAART-related (NANHR) events have become the most frequent clinical events in HIV-infected patients with HAART. Methods: In the APROCO/COPILOTE cohort, 1281 patients were enrolled in 1997-1999 at the initiation of a protease inhibitor-containing antiretroviral regimen. All severe events (hospitalization or death) were reviewed by a validation committee. Incidence and risk factors for NANHR events were analyzed using multivariate Cox models with CD4 and plasma HIV RNA as time-dependent covariates. Results: Among 1231 patients (median follow-up, 7 years), 713 NANHR events were recorded (incidence, 10.5/100 patient-years). Most frequent first-occurring NANHR events were (mainly bacterial airway) infections (196 events, 27%), cancer-related (68, 9.5%), cardiovascular (68, 9.5%) and psychiatric events (61, 8.5%). They were significantly more frequent in patients older than 60 (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.3-3.2), co-infected with HCV (HR, 1.7; 95% CI, 1.4-2.1), with CD4 below 100 cells/mm3 (HR, 2.5; 95% CI, 1.8-3.6) and with HIV RNA level above 10 000 copies/mL (HR, 1.9; 95% CI 1.5-2.5). Infections represented 41.5% and 42.4% of the events occurring at CD4 below 100 cells/mm3 and at HIV RNA level above 10 000 copies/mL, respectively. Conclusions: Non-AIDS non-HAART severe clinical events, especially bacterial infections, may be favored by persistent immunosuppression and virological replication.