One hundred-four women with symptoms of lower urinary tract inflammation (dysuria, frequency, and suprapubic tenderness) were randomly assigned to one of two treatment regimens: either a single dose of two double-strength trimethoprim-sulfamethoxazole, (TMP-SMZ) tablets (320 mg of TMP and 1,600 mg of SMZ) or conventional therapy of one double-strength tablet (160 mg of TMP and 800 mg of SMZ) twice a day for 10 days. Eighty-one patients had true bacteriuria; 93% of the infections were eradicated by single-dose therapy and 95% by conventional therapy. Results of an antibody-coated bacteria assay showed no correlation with therapeutic outcome. Clinically important side effects were observed in 4% of patients treated with single-dose therapy and 24% (P <0.05) of those treated with conventional therapy. Twenty-three patients had acute urethral syndrome, 14 with and nine without pyuria on initial urinalysis. The 14 with pyuria responded to antimicrobial therapy, whereas those without pyuria did not. This response pattern is consistent with recent data concerning the etiology of acute urethral syndrome. It is concluded that single-dose TMP-SMZ therapy is effective, easily administered, inexpensive, and free from significant side effects, and that it should have broad applicability in the treatment of women with acute, uncomplicated urinary tract infection.