We have previously demonstrated that six weeks of prophylaxis with interferon-alpha delays cytomegalovirus excretion and decreases viremia in recipients of kidney transplants. In a double-blind trial to evaluate the effects of a longer course of prophylaxis, we gave either 3 X 10(6) units of interferon or placebo intramuscularly to 42 patients before transplant surgery was performed. After surgery, doses were given three times a week for six weeks and then twice a week for eight weeks (total of 102 X 10(6) units). Clinical signs of cytomegalovirus infection were markedly reduced in interferon recipients. These signs developed in 7 of 22 placebo recipients and 1 of 20 interferon recipients (P = 0.03). Opportunistic superinfections (Aspergillus fumigatus and Pneumocystis carinii) occurred only in patients given placebo. Cytomegalovirus-associated glomerulopathy developed in one interferon recipient and three placebo recipients. Survival of patients and grafts was equivalent in both treatment groups, and minimal toxicity was observed with interferon. In seropositive renal-transplant recipients, interferon-alpha affords effective prophylaxis against serious cytomegalovirus infections.