The reduction of risk of non-AIDS events after combined antiretroviral therapy (cART) initiation and the crude incidence rate (CIR) of these events in patients who control the viral load without cART (controllers) in a cohort of 574 antiretroviral-naive patients with a baseline CD4 T cell count above 500 cells/mm³ were assessed. Non-AIDS severe events were defined as a first admission to the hospital due to non-AIDS-defining malignancies, cardiovascular, neuropsychiatric, liver-related, or end-stage renal disease events. Potential determinants of non-AIDS/death events were studied using Cox regression models. Eighty-five non-AIDS/death events occurred during 6,062 persons-years of follow-up (PYFU) with a CIR of 1.4 per 100 PYFU. Factors associated with non-AIDS/death event were age (HR 3.4; 95% CI: 1.6-6.9), nadir CD4 below 350 cells/mm³ (HR 2.5; 95% CI: 1.4-4.6), and a last determination of viral load above the median (HR 1.9; 95% CI: 1.0-3.3). The CIR of non-AIDS/death events was 2.1 and 1.8 per 100 PYFU before and after cART in patients who started cART (n=446). A reduction of CIR of non-AIDS events after cART initiation was observed only in patients with a nadir of CD4 above 350 cells/mm³ (2.5 vs. 0.6 per 100 PYFU, p=0.004, and remained stable after cART in patients with a median nadir of CD4 below 350 cells/mm³. CIR was similar in elite, viremic, and noncontrollers (1.1, 1.0, and 1.5 per 100 PYFU, respectively, p=0.25). Reduction of CIR of non-AIDS events after cART initiation depends on nadir CD4 T cell count. Most of the controllers patients had a CIR similar to noncontrollers. These data support the early initiation of cART in HIV-infected patients.