This study evaluated whether trimethoprim-sulfamethoxazole (TMP-SMX) is effective for treatment of uncomplicated urinary tract infections (UTIs) due to TMP-SMX-resistant (TMP-SMX-R) pathogens. Healthy nonpregnant premenopausal women with symptomatic lower UTI were assessed for the presence of pyuria and bacteriuria; if either was present, a urine sample was cultured and TMP-SMX was prescribed. Clinical and microbiologic cure was assessed at days 5-9 and 28-42 after cessation of therapy. For 71%, of patients, cultures grew TMP-SMX-susceptible (TMP-SMX-S) microorganisms, and for 29%, cultures grew TMP-SMX-R organisms. Escherichia coli remained the predominant bacteria in both groups of cultures. At visit 2, microbiological cure had been achieved in 86% of the patients in the TMP-SMX-S group and 42% of those in the TMP-SMX-R group. Similar differences were found at visit 3 by clinical evaluation. Treatment with TMP-SMX of uncomplicated UTI caused by TMP-SMX-R microorganisms results in microbiologic and clinical failure. In high-resistance areas, TMP-SMX should not be the empiric drug of choice for uncomplicated UTI.