Urinary tract infection (UTI) during the four months after renal transplantation occurs in 30%-40% of recipients at the Massachusetts General Hospital and is often associated with gram-negative bacteremia, significant graft dysfunction, and relapse. Of these "early" UTIs, 90% affect the graft itself. In a randomized trial of prophylaxis of UTI with trimethoprim-sulfamethoxazole (TMP-SMZ), 52 consecutive allograft recipients received either no prophylaxis or one TMP-SMZ tablet (160 mg of TMP plus 800 mg of SMZ) daily for four months, beginning on removal of the Foley catheter (usually during the first four days after transplantation). Three of the first five patients given TMP-SMZ developed oral candidiasis; they and all subsequent recipients of TMP-SMZ were given oral mycostatin throughout prophylaxis. Two of 26 patients (8%) taking TMP-SMZ developed UTIs; 10 of 26 patients (38%) not taking the drug developed UTIs with evidence of graft infection (P less than 0.05). The two groups were comparable in age, sex, history of UTI before transplantation, type of donor, type of ureteral anastomosis, and antibiotic use for other types of infection. Only one complication, a skin eruption, was observed among patients taking TMP-SMZ and mycostatin. It is concluded that TMP-SMZ is well tolerated and effective prophylaxis in this setting.