Oral ganciclovir prophylaxis decreases the incidence of cytomegalovirus (CMV) disease among persons infected with the human immunodeficiency virus (HIV), but universal prophylaxis is not cost-effective. We evaluated urine and peripheral blood mononuclear cell cultures, a qualitative and quantitative antigenemia assay, and a commercially available CMV DNA hybridization assay for their ability to predict CMV disease in 138 HIV-infected patients. During a median follow-up of 10 months, 23 patients (17%) developed CMV disease. The sensitivity, specificity, positive predictive value, negative predictive value, and mean lead times for the antigenemia assay (with use of a threshold of 8 positive cells per 10(5) peripheral blood mononuclear cells as a positive) were 74%, 91%, 63%, 95%, and 95 days, respectively. Corresponding figures for the DNA hybridization assay were 91%, 64%, 34%, 97%, and 152 days. These assays can identify patients at increased risk of CMV disease and should allow a strategy of preemptive therapy to be tested.