OBJECTIVES: Most patients with chronic obstructive pulmonary disease (COPD) experience exacerbations, which are associated with high healthcare costs. In the outpatient setting, exacerbations are frequently treated with antibiotics, despite the limited evidence on their short or long-term benefit. This study aims to investigate if the antibiotic doxycycline added to the standard therapy prednisolone is cost-effective for treating COPD acute exacerbations compared to prednisolone alone over a 2-year period. METHODS: An economic evaluation from the societal perspective was performed alongside a 2-year randomized controlled trial. Healthcare utilization and loss of productivity were measured using retrospective questionnaires and clinical report forms. Missing data were imputed using multiple imputations by chained equations. Bootstrapping was employed to estimate statistical uncertainty surrounding cost-effectiveness outcomes. A sensitivity analysis from the healthcare perspective was performed. The primary outcomes were costs per quality adjusted life year (QALYs) and per exacerbation prevented. RESULTS: There were significant differences in costs (€ 904, 95% CI €-154 to €1895) QALYs (0.02, 95% CI -0.04 to 0.07), and exacerbations (0.01, 95% CI -0.15 to 0.13) between the doxycycline and the placebo group. Cost-effectiveness acceptability curves showed that the probability that doxycycline is cost-effective compared to placebo is 52% and 43% at a willingness to pay of 30,000 € per QALY and exacerbation avoided, respectively. The sensitivity analysis showed similar results from the healthcare system perspective. CONCLUSIONS: Doxycycline added to prednisolone is not cost-effective compared to prednisolone alone for treating COPD exacerbations in the outpatient setting.