Rationale: The role of antibiotics in acute exacerbations is controversial and their efficacy when added to systemic corticosteroids is unknown. Objectives: We conducted a randomized, placebo-controlled trial to determine the effects of doxycycline in addition to corticosteroids on clinical outcome, microbiological outcome, lung function and systemic inflammation in patients hospitalized with an acute exacerbation of COPD. Methods: We enrolled 265 exacerbations out of 223 patients defined by increased dyspnea, increased sputum volume with or without increased sputum purulence. Patients received 200mg of oral doxycycline or matching placebo for seven days in addition to systemic corticosteroids. Clinical and microbiological response, time to treatment failure, lung function, symptom scores and serum C-reactive protein were assessed. Measurements and Main Results: At day 30, clinical success was similar in intention-to-treat (ITT) patients (Odds ratio [OR], 1.3; 95% confidence interval [CI], 0.8 to 2.0) and per-protocol (PP) patients. Doxycycline showed superiority over placebo on clinical success at day 10 in ITT patients (OR, 1.9; 95% CI, 1.1 to 3.2), but not in PP patients. Doxycycline was also superior on clinical cure at day 10, microbiological outcome, use of open label antibiotics and symptoms. There was no interaction between the treatment effect and any of the subgroup variables (lung function, type of exacerbation, serum CRP and bacterial presence). Conclusions: While equivalent to placebo on clinical success at day 30, doxycycline showed superiority on clinical success and clinical cure at day 10, microbiological success, the use of open label antibiotics and symptoms. (ClinicalTrials.gov #NCT00170222.)