One hundred sixty-three women with uncomplicated acute lower urinary tract infections were included in a multicenter randomized study comparing cefpodoxime-proxetil (one 100-mg tablet twice daily) with trimethoprim-sulfamethoxazole (one double-strength tablet [160/800 mg] twice daily) for 3 days. A total of 30 women in both arms were excluded from the study for various reasons. At 4 to 7 days after the discontinuation of therapy, 62 of 63 (98.4%) cefpodoxime-proxetil recipients and 70 of 70 (100%) trimethoprim-sulfamethoxazole patients were clinically cured and demonstrated bacteriological eradication, respectively. At 28 days after treatment, 48 of 55 (87.3%) and 43 of 50 (86%) cefpodoxime-proxetil recipients as well as 51 of 60 (85%) and 42 of 50 (84%) trimethoprim-sulfamethoxazole recipients were clinically cured and demonstrated bacteriological eradication, respectively. Independently of the prescribed regimen, a significant difference (P < 0.001) in failure rates was observed only for patients with a previous history of three or more episodes of acute cystitis per year. With the exception of one patient in the trimethoprim-sulfamethoxazole arm who discontinued therapy because of gastrointestinal pain, both antimicrobials were well tolerated. In conclusion, cefpodoximeproxetil treatment for 3 days was as safe and effective as trimethoprim-sulfamethoxazole for 3 days for the treatment of uncomplicated acute cystitis in women.Among pre-and postmenopausal women, uncomplicated lower urinary tract infections (UTIs) constitute a common reason for seeking medical assistance. Short-course, 3-day therapeutic regimens with trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolones have been proven to be as effective as longer courses of Ն5 days and are widely used (13,22). Their advantages are based on increased patient compliance, with decreased adverse effects, decreased costs, and deceased rates of resistance development among the gut and vaginal flora (20). However, the increasing rates of TMP-SMX resistance in the community worldwide (2, 10, 17) as well as the adverse effects of TMP-SMX (3) are causes for concern. Thus, alternative short-course antimicrobial regimens are required. Unfortunately, amoxicillin and older cephalosporins are efficacious only when they are administered for Ն5 days, while nitrofurantoin requires at least 7 days of therapy (16).Cefpodoxime-proxetil is an orally administered prodrug which is absorbed and deesterified by the intestinal mucosa to release the advanced cephalosporin cefpodoxime, which has approximately 50% systemic bioavailability (5). Cefpodoxime absorption is significantly increased by food, whereas it is reduced by agents that elevate the gastric pH (5). It has a broad spectrum of antibacterial activity encompassing both gramnegative and gram-positive bacteria and is stable against the most commonly found plasmid-mediated beta-lactamases including the TEM-2 and SHV-1 enzymes (5, 23); however, cefpodoxime is hydrolyzed by SHV-2, which is produced by some Klebsiella pneumon...