To evaluate the efficacy and safety of single-dose 2.0 g azithromycin (ZSR) in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), we retrospectively reviewed all patients with AE-COPD who were treated with ZSR. In comparison with patients who received intravenous therapy for AE-COPD, the clinical cure rate, length of stay in hospital, and medical costs were evaluated. A total of 29 patients thus were eligible for this study. Clinical cure rates of ZSR and intravenous therapy for the treatment of AE-COPD were 83.3% (n = 12) and 88.2% (n = 17), respectively, between the groups (P = 1.000). No severe adverse events were found in either group. The ZSR and intravenous groups averaged 9.9 and 12.5 days of admission, respectively. Length of admission for clinical success cases was much shorter for patients who received ZSR than patients who received intravenous therapy (6.2 vs. 11.9 days, P = 0.038). Medical costs were less for the group receiving ZSR than for the intravenous therapy group. We suggest ZSR can achieve near-perfect compliance and could be one of the tools in the treatment of AE-COPD.