We prospectively followed up 589 patients to evaluate the relationship of anti-cytomegalovirus (CMV) treatment and immune reconstitution in response to highly active antiretroviral therapy (HAART) on the mortality risk of patients with CMV retinitis and acquired immune deficiency syndrome. The use of HAART was associated with an 81% lower mortality rate (95% confidence interval [CI], 74%-86%); it was 96% lower (95% CI, 92%-98%) for those who developed immune recovery and 49% lower (95% CI, 30-63%) for those who did not. Using time-updated multivariate analysis, current systemic anti-CMV treatment was independently associated with a 28% lower mortality rate (95% CI, 8%-43%). On the basis of these results, for patients who continue to have profound immunodeficiency despite HAART, the continued use of HAART and systemic anti-CMV therapy is predicted to reduce the risk of mortality by 65%, over and above the benefits of Pneumocystis carinii and Mycobacterium avium prophylaxis.