To examine the costs and consequences of prophylaxis against cytomegalovirus (CMV) infection, we developed a compartmental model of the natural history of late-stage HIV disease. We used data on the progression of illness, economic costs, the incidence of infections, the efficacy and toxicity of therapy, and patient quality of life from national cohort studies, randomized clinical trials, and resource-utilization surveys. We found that CMV prophylaxis confers additional quality-adjusted life-years at a lower-bound, marginal cost of $160,000. While this cost-effectiveness result compares unfavorably with alternative uses of scarce resources, it is sensitive to assumptions regarding the price of therapy and the incidence of infection.