Objective: To evaluate the effect of drug-resistant cytomegalovirus (CMV) on survival among patients with CMV retinitis. Design: Prospective cohort study during 1993 to 2003. Participants: We included 266 patients with AIDS and newly diagnosed CMV retinitis treated with either ganciclovir or foscarnet. Methods: Data on ganciclovir and foscarnet resistance were obtained from blood and urine specimens collected at regular, predetermined intervals. The effect of resistant CMV on mortality was evaluated with a time-dependent Cox proportional hazard model. Main Outcome Measures: Mortality. Results: The median survival of the entire cohort was 12.6 months. Analysis of risk factors for mortality demonstrated that resistant CMV was associated with an increased mortality (hazard ratio, 1.65; 95% confidence interval, 1.05-2.56; P = 0.032). Among the other parameters tested, only time since AIDS diagnosis was associated significantly with mortality, with a hazard ratio of 1.10 per year since AIDS diagnosis (P = 0.001). Conclusions: Resistant CMV is associated with increased mortality among patients with AIDS being treated for CMV retinitis. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.