OBJECTIVES: To estimate the cost-effectiveness of roflumilast (Daxas®) versus the most prescribed drug combination in Spain in the treatment of adult patients with severe chronic obstructive pulmonary disease (COPD) with a history of frequent exacerbations. METHODS: A Markov model was constructed to estimate the life time cost-effectiveness of roflumilast plus a long acting muscarinic antagonist (roflumilast + LAMA) versus the combination of LAMA with a long-acting beta agonist plus and an inhaled corticosteroid (LAMA+LABA/ICS). Outcomes were expressed as the incremental cost per exacerbation avoided from the Spanish National Health System perspective using a life-time horizon (30 years). Other health outcomes in the model include quality-adjusted life year (QALY) gained and life years (LY) gained. The key inputs to the model are based on roflumilast pivotal clinical trials and published epidemiological and population data. Uncertainty in the model’s parameters was examined by sensitivity analysis. RESULTS: The results of the economic analysis have demonstrated that over the lifetime of the treatment of patients with severe COPD and associated chronic bronchitis with a history of frequent exacerbations, the roflumilast + LAMA strategy will cost 3468 € less than using LAMA + LABA/ICS. Over a lifetime a patient treated with a roflumilast + LAMA is estimated to have 1.23 exacerbations less and 0.129 more QALYs that a patient treated with LAMA + LABA/ICS. Therefore, the roflumilast treatment arm appears to be the dominating option. The sensitivity analyses showed that the variable that has the most impact on the ICER results is the relative risk of exacerbations. CONCLUSIONS: Roflumilast + LAMA offers a cost-effective option for the maintenance treatment of severe COPD associated with chronic bronchitis in patients with a history of frequent exacerbations compared with LAMA + LABA/ICS.