Cytomegalovirus (CMV) disease, an opportunistic complication in patients with AIDS, causes substantial morbidity and has high treatment costs. Although prevention of this disease is highly desirable, incremental cost-effectiveness estimates for proposed prophylactic strategies in the era prior to the availability of highly active antiretroviral therapy (HAART) were unfavourable relative to other specific antimicrobial prophylactic strategies in patients with AIDS. With the availability of HAART, several inputs upon which previous estimates of the incremental cost-effectiveness ratio for anti-CMV prophylaxis were based probably changed substantially. To assess the incremental cost effectiveness of prophylaxis in the HAART era, data are needed on visual outcomes and utility for patients with CMV retinitis and AIDS, on better strategies for identifying subpopulations at high risk for CMV disease and on the prophylactic efficacy of valganciclovir. Cost-effectiveness analysis could potentially contribute by exploring thresholds of population risk, prophylactic effectiveness, and drug pricing in order to identify conditions under which prophylaxis for CMV disease in patients with AIDS could potentially become cost effective.