Thirteen women and two preadolescent girls who suffered recurrences after six months of prophylaxis with trimethoprim (TMP; 40 mg) and sulfamethoxazole (SMZ; 200 mg) taken thrice weekly at bedtime were enrolled in a 24-month study of prophylaxis with the same region. During 29.1 cumulative patient-years of prophylaxis, two infections due to Escherichia coli and one each due to Staphylococcus epidermidis and Streptococcus faecalis occurred (0.14 infection/patient-year). MICs for these isolates were less than or equal to 2 micrograms of TMP/ml and greater than 512 micrograms of SMZ/ml. During prophylaxis, 106 of 116 cultures from the periurethral area and 66 of 97 cultures from the anal and canal yielded no aerobic gram-negative bacilli. In three patients, the periurethral area was colonized with aerobic gram-negative bacilli with MICs of greater than or equal to 2 micrograms of TMP/ml. Thirteen patients were followed after the discontinuation of prophylaxis. Eight suffered recurrences, seven with organisms susceptible to TMP. After one year the remaining five had experienced no recurrences. It is concluded that long-term prophylaxis with 40 mg of TMP and 200 mg of SMZ thrice weekly is an effective, well-tolerated regimen that can maintain an infection-free state in women with histories of frequent urinary reinfections.