Escherichia coli infections are a common cause of respiratory disease in turkeys. To control these respiratory infections in turkeys, drinking water treatment with enrofloxacin is widely used. The current treatment schedule advises a 5-d treatment at 10 mg/kg of BW. Because enrofloxacin exerts a concentration-dependent activity, it might be useful to provide this 50 mg/kg total dose in a single-day treatment regimen. Therefore, we assessed whether a single-day treatment schedule with 50 mg/kg of BW was clinically equivalent to the advised multiple-day treatment schedule with 10 mg/kg of BW for 5 d. For this purpose, 3 groups of seventeen 22-d-old turkeys were experimentally inoculated with avian metapneumovirus and 3 d later with E. coli. One group received 10 mg of enrofloxacin/kg of BW in the drinking water for 5 successive days. The second group received 50 mg of enrofloxacin/kg of BW for 20 h in the drinking water. The third group was enclosed as an untreated positive control group. Both the multiple- and the single-day enrofloxacin treatment regimens reduced E. coli multiplication in the respiratory tract tissues (turbinates, trachea and lung), but the 5-d treatment with 10 mg of enrofloxacin/kg in turkeys provided the best results by shortening the course of clinical disease, by eliminating E. coli from the respiratory tract without remultiplication, and by reducing macroscopic lesions. The efficacy of the single-day treatment did not equal that of the 5-d treatment, possibly by not eliminating E. coli from the respiratory organs, which made it possible for the remaining bacteria to reemerge in those organs. None of the used treatment regimens promoted the selection of bacterial clones with reduced susceptibility or resistance.