Infectious Diseases Society of America guidelines state that uncomplicated urinary tract infections (UTIs) should be treated empirically with trimethoprim-sulfamethoxazole (TMP-SMZ), unless the community resistance among uropathogens exceeds 10%-20%, in which case a fluoroquinolone (FQ) should be used. However, the data to support this threshold are limited. We performed a cost-minimization and sensitivity analysis to determine what level of TMP-SMZ resistance in a community should trigger FQ use. The mean cost of empirical treatment with TMP-SMZ was US$92 when the proportion of resistant Escherichia coli was 0%, $106 when it was 20%, and $120 when it was 40%. The mean cost of empirical FQ treatment was $107 at current levels of FQ resistance. When >22% of E. coli in a community are TMP-SMZ-resistant, empirical FQ therapy becomes less costly than TMP-SMZ therapy. Treatment guidelines for empirical treatment of UTIs may need modification, and the threshold trigger for empirical FQ use should be raised to >20% TMP-SMZ resistance.