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It is often difficult to determine the cause of chronic obstructive pulmonary disease (COPD) exacerbations, and antibiotics are frequently prescribed. This study conducted an observational cost-effectiveness analysis of prescribing antibiotics for exacerbations of COPD based on routinely collected data from patient electronic health records. A cohort of 45 375 patients aged 40 years or more who attended their general practice for a COPD exacerbation during 2000–2013 was identified from the Clinical Practice Research Datalink. Two groups were formed (“immediate antibiotics” or “no antibiotics”) based on whether antibiotics were prescribed during the index general practice (GP) consultation, with data analysed according to subsequent healthcare resource use. A cost-effectiveness analysis was undertaken from the perspective of the UK National Health Service, using a time horizon of 4 weeks in the base case. The use of antibiotics for COPD exacerbations resulted in cost savings and an improvement in all outcomes analysed; i.e. GP visits, hospitalisations, community respiratory team referrals, all referrals, infections and subsequent antibiotics prescriptions were lower for the antibiotics group. Hence, the use of antibiotics was dominant over no antibiotics. The economic analysis suggests that use of antibiotics for COPD exacerbations is a cost-effective alternative to not prescribing antibiotics for patients who present to their GP, and remains cost-effective when longer time horizons of 3 months and 12 months are considered. It would be useful for a definitive trial to be undertaken in this area to determine the cost-effectiveness of antibiotics for COPD exacerbations.