We developed a mathematical simulation model to anticipate outcomes from an upcoming trial of targeted, preemptive cytomegalovirus (CMV) therapy in high-risk, human immunodeficiency virus (HIV)-infected patients identified by means of CMV polymerase chain reaction screening. We estimated the costs and consequences of CMV prophylaxis in patients with CD4(+) counts < or =100 cells/microL under various assumptions regarding disease progression, complication rates, drug effects, and costs. Without CMV preemptive therapy, lifetime costs average $44,600 with expected duration of survival of 19.16 quality-adjusted life-months and 213 CMV cases per 1000 patients. Targeted preemptive therapy with orally administered valganciclovir increases costs and duration of survival to $46,900 and 19.63 quality-adjusted life-months, respectively. CMV cases decrease to 174 per 1000 patients. The cost per quality-adjusted life-year gained is $59,000. This result compares favorably with other strategies in end-stage HIV disease but hinges on valganciclovir cost and efficacy assumptions and the absence of minimally effective salvage antiretroviral therapy for HIV. The upcoming trial should resolve the clinical uncertainty surrounding some of these assumptions.