This multicentre prospective cohort study by the EuroSIDA study group was designed to determine the factors affecting the incidence of cytomegalovirus (CMV) end-organ disease (CMVD) and the rate of survival after diagnosis in patients with AIDS during the years 1994-2001. This period includes two eras, the pre-HAART era and the HAART era, because HAART affects the natural history of HIV infection, especially with respect to opportunistic infections, including CMV infection. Clinical and laboratory data were collected from the charts of 8,556 patients in 63 AIDS clinics in Europe. A total of 707 patients had CMVD at recruitment and at follow-up: 449 with retinitis (CMVR), 190 with extraocular CMV disease (EOCMVD), and 58 with both. Of the cases of EOCMVD, 66% involved the gastrointestinal tract and 17% the central nervous system. Of patients with a CD4+ count of ≤200 mm-3 initially, 1.8% on HAART developed CMVD within a 24-month period, as compared to 11.1% on dual therapy and 14.3% without treatment (P<0.0001). There were highly significant differences in survival according to the calendar year (P<0.0001), with mortality declining from 79% during the years 1994-1995 to 42% in 2000-2001. The incidence of death after any CMVD was 28.4 per 100 patient-years of follow-up. Median survival of CMVR patients and EOCMVD patients was 11 and 7 months, respectively, the prognosis being better among patients with gastrointestinal rather than neurological CMVD. The initiation of HAART was associated with a 37% decrease in mortality (P<0.05). Eighteen percent of all deaths were caused by EOCMVD itself. This study describes a decline in the incidence and mortality of CMVR and EOCMVD during the HAART era of the HIV epidemic. It furthermore serves as a reminder of the importance of EOCMVD as a cause of morbidity and mortality in AIDS in the pre-HAART era.