OBJECTIVES: Consistent with recommendations from professional societies, two of the most common approaches to empiric community-acquired pneumonia (CAP) therapy are sequential therapy with IV azithromycin plus IV ceftriaxone followed by oral azithromycin, and IV levofloxacin followed by oral levofloxacin. The purpose of this study is to asses the economic impact of those regimens in a Spanish setting using an economic model. METHODS: A cost-minimization analysis was performed from the hospital perspective as the same efficacy was observed. Resource use was based on the results from a randomized, open-label multicenter trial (Zervos. Treat Respir Med 2004). Mean length of stay (LOS) and general medical wards LOS were 8.8 and 7.4 days in the levofloxacin group vs. 7.0 and 5.7 days in the azithromycin group. Days on study medication was 13.7 IV+2.9 oral and 3.2 IV+12.2 oral in the levofloxacin and azithromycin group, respectively. Only in-hospital (€2007) direct costs per-patient were considered: hospitalization costs (ICU-general ward), drug acquisition cost (at their hospital selling prices) and administration costs. Costs were obtained from Spanish databases. Univariate and bivariate threshold sensitivity analyses were carried out to test the robustness of the model. RESULTS: Mean cost per patient treated is estimated to be €2666.0 with azithromycin plus ceftriaxone and €3532.9 with levofloxacin, with an incremental cost of €866.9. Azithromycin-LOS reduction was the main cause for most of the difference cost. The sensitivity analysis showed that levofloxacin would be less costly than azithromycin only if levofloxacin-LOS were lower than 4.8 days. The robustness of the model is related to daily cost and LOS. CONCLUSION: According to this model, azithromycin plus ceftriaxone is less costly than levofloxacin-monotherapy for treating community-acquired pneumonia patients requiring hospitalization in Spain. The cost benefit attributable to azithromycin depends on its role in reducing the length of stay.