OBJECTIVE: To compare mortality rates in combination antiretroviral therapy (cART)-treated HIV-infected adults with mortality in the general population according to the level of CD4 cell count reached and the duration of exposure to cART. METHODS: HIV-infected adults initiating a protease inhibitor-containing treatment between 1997 and 1999 were selected in the Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS) APROCO and AQUITAINE cohorts. CD4 cell counts were estimated during follow-up using a 2-phase mixed linear model. Standardized mortality ratios (SMRs) were computed in reference to the 2002 French population rates, overall and for the time period spent with a CD4 count >or=500 cells/mm3. To identify if and when mortality rates reached values of the general population, SMRs were computed successively with truncation at each year of follow-up. RESULTS: The 2,435 adults (77% men, baseline median age = 36 years, and baseline median CD4 count = 270 cells/mm3) had a median follow-up of 6.8 years. The SMR was 7.0 (95% confidence interval [CI]: 6.2 to 7.8). During the 5,402 person-years spent with a CD4 count >or=500 cells/mm3, the mortality reached the level of the general population after the sixth year after cART initiation (SMR = 0.5, 95% CI: 0.1 to 1.6). CONCLUSION: Although overall mortality was higher in cART-treated HIV-infected adults, a subgroup with especially good prognosis can be identified, and these characteristics should be targeted for long-term treatment.