A total of 331 college-age women with urinary tract infections were studied. These women were assigned randomly to the following groups: 50 patients treated with 400 mg of trimethoprim (TMP) per day for 14 days (designated the TMP400/ 14d group); 50 treated with 2.0 g of sulfisoxazole (SZ) per day for 14 days (SZ/14d group); 120 treated with 200 mg of TMP per day for 10 days (TMP200/10d group); and 111 treated with 2.0 g of SZ per day for 10 days (SZ/lOd group). By the last day of therapy, clinical and bacteriological cure rates were 100% in the TMP400/14d, SZ/14d, and TMP200/lOd groups and 97.1% in the SZ/lOd group. At 1 week after therapy ended, the initial urinary pathogens remained eradicated in 100% of the TMP400/14d group, 98.2% of the TMP200/lOd group, 95.6% of the SZ/14d group, and 98.0% of the SZ/lOd group. At 4 weeks after therapy ended, the clinical cure rates were 92.0% in the TMP400/14d group, 92.0% in the SZ/14d group, 89.0% in the TMP200/lOd group, and 90.0% in the SZ/lOd group. At 4 and 24 weeks after therapy ended, the recurrence rates in the four treatment groups did not differ significantly. The antibody-coated bacteria test localized 39.5% of the infections to kidneys and 56.8% of the infections to bladders. Neither symptoms nor responses to therapy were correlated with the antibody-coated bacteria test results. Both TMP at a dose of 200 mg/day and SZ were tolerated well. TMP at a dose of 400 mg/day was associated with a skin rash in 24% of the patients receiving this therapy. TMP suppressed fecal Escherichia coli. SZ increased the number of sulfa-resistant fecal isolates; however, this phenomenon did not affect the rate of sulfa-resistant recurrences.Trimethoprim (TMP), a 2,4-diaminopyrimidine, is an antimicrobial agent which acts against a wide variety of bacterial species by selectively inhibiting microbial folate metabolism. TMP competitively inhibits bacterial dihydrofolate reductase and consequently blocks the formation of tetrahydrofolate and deoxyribonucleic acid synthesis. The inhibitory activity of TMP is enhanced by adding a sulfonamide, which acts in a prior step to prevent the formation of dihydrofolate (5, 6). Furthermore, Darrell et al. reported that the presence of a sulfonamide could reduce the emergence of TMP resistance when bacteria were exposed in vitro to low levels of TMP, provided that they were initially sulfa sensitive (11). Consequently, TMP has been used extensively in combination with sulfamethoxazole for the treatment of a variety of infections, including urinary tract infections (UTIs) (7,9,26). Interest in the synergistic effects of TMP and the sulfonamides diverted attention from the activity of TMP as an antibacterial agent in its own right. Preliminary descriptions of TMP as the sole therapeutic agent against adult UTIs have been encouraging (4,17,21,23).In this study the efficacy and safety of TMP were compared with the efficacy and safety of sulfisoxazole (SZ)