Our objectives were to determine the factors associated with the occurrence of a first episode of cytomegalovirus (CMV) disease in an HIV-infected population and to estimate the overall impact of CMV disease on survival. The study population consisted of the 3525 patients included in the Aquitaine Cohort between 1985 and December 31, 1993. Eligible patients (n = 1868) must have had at least one CD4+ lymphocyte count of <200 cells/mm3 during follow-up, which represents the baseline period. CMV disease manifestations were investigated using standardized definitions. A Cox proportional hazards regression analysis was used to determine the factors independently associated with the probability of developing a first episode of CMV infection and the probability of death. During follow-up, 111 patients presented with a first episode of CMV disease. Four factors were independently associated with the onset of CMV disease: older age at baseline (risk ratio [RR] = 1.03 by a 1-year increase; 95% confidence interval [CI] = 1.02-1.05), homosexuality (RR = 1.90; CI = 1.18-3.02), the progression to a CD4+ lymphocyte count <50/mm3 (RR = 10.58; CI = 5.58-20.05), and the occurrence of toxoplasmosis (RR = 3.00; CI = 1.97-4.57) or a neurologic disease (RR = 2.59; CI = 1.38-4.86) during follow-up. After other predictors were controlled for, CMV disease was associated with a high risk of death in the cohort (RR = 1.58; CI = 1.24-1.94). The development of prophylactic strategies for CMV disease for selected groups of HIV-infected patients must be a priority to improve their quality of life.