Consecutive adult patients admitted to the hospital with community-acquired pneumonia from January 2000 to September 2003 were included in this prospective observational cohort study. A total of 459 patients, 259 treated with levofloxacin in single drug therapy at a dose of 500 mg once a day and 209 with the combination of ceftriaxone plus clarithromycin at a dose of 2 g once a day and 500 mg every 12 h, respectively, were included. The hospital admission decision was made using a clinical guideline based on the Pneumonia Severity Index (PSI). Fifteen (6%) patients died in the group treated with levofloxacin in single drug therapy and 25 (12%) in the group treated with ceftriaxone plus clarithromycin (P = 0.024). The mortality differences between both treatment groups, adjusted by the PSI score, show an OR of 0.39 (95% CI 0.17-0.87). There were no statistically significant differences between the duration of treatments or hospital stay. These data suggest that levofloxacin as single drug therapy is more effective than the combination of ceftriaxone plus clarithromycin in the treatment of moderate to severe pneumonia that requires hospitalization.