Introduction: Duration of antibiotic treatment in acute exacerbation of COPD (AECOPD) is most commonly based on expert opinion. Typical administration periods range from 5 to 7 days. A 2-day course with levofloxacin was not previously assessed. We performed a randomized clinical trial to evaluate the efficacy of 2-day versus 7-day treatment with levofloxacin in patients with AECOPD.Methods: Patients with AECOPD were randomized to receive levofloxacin for 2 days and 5 days placebo (n=155) or levofloxacin for 7 days (n=155). The primary outcome measure was cure rate, and secondary outcome included need for additional antibiotics, ICU admission, reexacerbation rates and exacerbation free interval (EFI) within one year follow-up. Results: In ITT analysis, cure rate was 79.3% (n=123) and 74.2% (n=115) respectively in 2-day and 7-day groups. In PP analysis, cure rate was 78% (n=92) and 69% (n=82) respectively in 2-day and 7-day groups. The difference between both groups was not significant. The need for additional antibiotics and ICU admission rates were not significantly different between both groups. One-year reexacerbation rate was 34.8% (n=54) in 2-day group versus 29% (n=45) in 7-day group (p=0.19); the EFI was 121 days (interquartile range, 99-149) versus 110 days (interquartile range, 89-132) in 2-day and 7-day treatment groups respectively (p=0.73). No difference in adverse effects was detected.Conclusion: Levofloxacin once daily for 2 days is not inferior to 7 days with respect to cure rate and hospital readmission in COPD exacerbations. Our finings would improve patient compliance and reduce the incidence of bacterial resistance and adverse effects.