Emerging antimicrobial resistance among uropathogens makes the management of acute uncomplicated cystitis increasingly challenging. Few prospective data are available on the risk factors for resistance to trimethoprim- sulfamethoxazole (TMP-SMX), the drug of choice in most settings. In order to evaluate this, we prospectively enrolled women 18 to 50 years of age presenting to an urban primary care practice with symptoms of cystitis. Potentially eligible women provided a urine sample for culture and completed a questionnaire regarding putative risk factors for TMP-SMX resistance. Escherichia coli isolates were tested for clonal group A (CGA) membership by a fumC-specific PCR. Of 165 women with cystitis symptoms, 103 had a positive urine culture and were eligible for participation. E. coli was the predominant uropathogen (86%). Fifteen (14.6%) women had a TMP-SMX-resistant (TMP-SMXr) organism (all of which were E. coli). Compared with the women who had a TMP-SMX-susceptible organism, women in the TMP-SMXr group were more likely to have traveled (odds ratio [OR], 15.4; 95% confidence interval [CI], 4.4 to 54.3; P < 0.001) and to be Asian (OR, 6.1; 95% CI, 1.0 to 36.4; P = 0.048). CGA was also independently associated with TMP-SMX resistance (OR, 105; 95% CI, 6.3 to 1,777.6; P = 0.001). No association with TMP-SMX resistance was demonstrated for the use of either TMP-SMX or another antibiotic in the past 3 months or with having a child in day care. Among these women with acute uncomplicated cystitis, Asian race and recent travel were independently associated with TMP-SMX resistance. TMP-SMXr isolates were more likely to belong to CGA. Knowledge of these risk factors for TMP-SMX resistance could facilitate the accurate selection of empirical therapy.