OBJECTIVE The authors previously conducted a pilot, dose-escalating study which suggested that a 20-micrograms dose of intravitreal cidofovir (HPMPC) may be safe and effective in treating cytomegalovirus (CMV) retinitis in humans. The purpose of this series is to expand the authors' prior experience with the 20-micrograms dose of cidofovir as the sole treatment for CMV retinitis in patients with acquired immune deficiency syndrome. METHODS The study design was an unmasked consecutive case series trial in a single-center institutional retina referral practice. Eligible patients with acquired immune deficiency syndrome had active CMV retinitis in at least one eye and no evidence of extraocular CMV disease. Patients received a 20-micrograms cidofovir trans pars plana injection and were treated with concomitant oral probenecid. Retreatments were performed for progression of retinitis as determined by serial fundus photographs judged independently by three observers. The primary outcome was time to retinitis progression determined by Kaplan-Meier analysis. Both globes of one patient who had unilateral retinitis were examined pathologically. RESULTS There were 37 cidofovir injections in 24 eyes of 17 patients. The median time to retinitis progression after the initial 24 injections was 55 days. The median time to retinitis progression after 8 repeat cidofovir injections was 63 days. There was a significant decrease in intraocular pressure from baseline to both 2 and 4 weeks after injection. A mild to moderate iritis developed in five (20.8%) eyes that responded well to topical medications. Results of histopathologic examination of one treated globe did not show any significant toxic effects. CONCLUSIONS This study demonstrates that prolonged arrest of the progression of CMV retinitis may be obtained with a single 20-micrograms cidofovir intravitreal injection. In addition, the effect of the drug appears to be maintained after a second injection. The effects of cidofovir in causing uveitis and a slight lowering of the intraocular pressure require further study.