A randomized, open, coordinated multi-center trial compared the bacteriological and clinical efficacy and safety of orally administered ceftibuten and trimethoprim-sulfamethoxazole (TMP-SMX) in children with febrile urinary tract infection (UTI). Children aged 1 month to 12 years presenting with presumptive first-time febrile UTI were eligible for enrollment. A 2:1 assignment to treatment with ceftibuten 9 mg/kg once daily (n = 368) or TMP-SMX (3 mg + 15 mg)/kg twice daily (n = 179) for 10 days was performed. Escherichia coli was recovered in 96% of the cases. Among the E. coli isolates, 14% were resistant to TMP-SMX but none to ceftibuten. In the modified intention-to-treat population, the bacteriological elimination rates at follow-up did not differ significantly between patients treated with ceftibuten and those treated with TMP-SMX [91 vs. 95%, with a 95% confidence interval (CI) for difference of -9.7 to 1.0]. However, the clinical cure rate was significantly higher among those treated with ceftibuten (93 vs. 83%, with a 95% CI for difference of 2.4 to 17.0). Adverse events were similar for both regimens and consisted mainly of gastrointestinal disturbances. In conclusion, ceftibuten is a safe and effective drug for the empirical treatment of febrile UTI in young children.