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To determine the rate of CD4 decline and the incidence of opportunistic infections (OIs) among antiretroviral therapy-naive South African HIV-infected patients and inform timing of OI prophylaxis.We used mixed-effect models to estimate CD4 cell decline by CD4 cell count strata in HIV-infected patients in the Cape Town AIDS Cohort between 1984 and 2000. Stratum-specific OI incidence per 100 person-years of observation was determined using incidence density analysis.Nine hundred seventy-four patients with 2 or more CD4 cell counts were included. CD4 counts declined by 47.1 cells/μL per year in the stratum with more than 500 cells/μL stratum, 30.6 cells/μL per year in the stratum with 351 to 500 cells/μL, and 20.5 cells/μL per year in the stratum with 201 to 350 cells/μL. Tuberculosis and oral candidiasis were the only OIs that occurred frequently in the stratum with more than 200 CD4 cells/μL. Rates of chronic diarrhea, wasting syndrome, tuberculosis, and oral and esophageal candidiasis increased in the stratum with less than 200 cells/μL, and rates of all OIs were highest in the stratum with 50 cells/μL or less.CD4 cell count declines were dependent on CD4 strata and can inform timing of clinic visits and treatment initiation in South Africa. Incidence rates of OIs suggest that targeted OI prophylaxis could prevent substantial HIV-related morbidity in South Africa.