Purpose To describe the course of cytomegalovirus (CMV) retinitis in patients with AIDS in the era of highly active antiretroviral therapy (HAART). Design Multicenter, prospective, observational study. Participants Two hundred seventy-one patients with AIDS and CMV retinitis. Methods Follow-up every 3 months with medical history, ophthalmologic examination, laboratory testing, and fundus photographs. Main outcome measure Second (contralateral) eye involvement among patients with unilateral disease and retinal detachment (RD). Results The overall rate of second eye involvement among patients with unilateral CMV retinitis was 0.07 per person-year (PY); among those with CD4+ T-cell counts of <50/μl it was 0.34/PY, compared with 0.02/PY among those with CD4+ T-cell counts of ≥200/μl ( P<0.0001). Risk factors for contralateral eye involvement included low CD4+ T-cell count and detectable CMV load. The overall rate of RD was 0.06/PY; among those with CD4+ T-cell counts of <50/μl it was 0.30/PY, compared with 0.02/PY among those with CD4+ T-cell counts of ≥200/μl ( P<0.0001). Risk factors for RD included a low CD4+ T-cell count and larger area of CMV retinitis. Conclusions Compared with the rates reported in the pre-HAART era of second eye involvement (∼0.40/PY) and RD (∼0.50/PY), the rates of these events were reduced among patients in the HAART era. However, among patients with CD4+ T-cell counts of <50/μl, the rates were more similar to those from the pre-HAART era.