This was a prospective, multicenter, double-blind, double-dummy, randomized, controlled, parallel-group, phase 3, non-inferiority clinical trial designed to compare oral zabofloxacin (367 mg once daily for 5 days) with moxifloxacin (400 mg once daily for 7 days) for the treatment of patients with COPD exacerbation. Three hundred and forty-five COPD patients with a moderate COPD exacerbation were enrolled in the study via the outpatient clinics at 31 university hospitals. Clinical PP analysis revealed that the clinical cure rate for zabofloxacin was 86.7% and that for moxifloxacin was 86.3% (the rate difference, 0.4%; 95% CI, -7.7-8.6%). ITT analysis revealed clinical cure rates of 77.1% and 77.3% (difference, -0.2%; 95% CI, -9.0-8.8%), respectively. These results confirm that zabofloxacin is not inferior to moxifloxacin. The favorable microbiological response rate for zabofloxacin was 67.4% and that for moxifloxacin was 79.5% (P = 0.22). Patients in the zabofloxacin group showed better patient-oriented outcomes, as measured by EXACT-PRO and CAT scores, than patients in the moxifloxacin group. Adverse drug reaction related to zabofloxacin occurred in 9.7% of cases and those related to moxifloxacin occurred in 9.6% of cases (P = 0.97). The dropout rate due to adverse events was 0.0% (0/175) in the zabofloxacin group and 1.8% (3/167) in the moxifloxacin group (P = 0.12). Oral zabofloxacin was not inferior to oral moxifloxacin for the treatment of patients with COPD exacerbation. This study is registered with ClinicalTrials.gov, numbers NCT01658020