We studied the cost-effectiveness of oral gemifloxacin with intravenous ceftriaxone followed by oral cefuroxime with or without a macrolide to treat patients hospitalized with community-acquired pneumonia. Data were prospectively collected as part of a randomized multicenter study. The costs evaluated included antimicrobial acquisition (1st level); plus preparation, dispensing, and administration costs, and treatment of antimicrobial-related adverse events and clinical failures (2nd level); plus per diem costs for hospital stay related to study drug administration (3rd level). At follow-up, clinical success was similar between gemifloxacin (76.9%)- and ceftriaxone (79.1%)-treated patients. The median 1st-level costs for gemifloxacin and ceftriaxone were $136 and $470 (P<0.001), respectively. For the 2nd level, these costs were $158 and $542 (P<0.001), and for the 3rd level, these were $5052 and $5789 (P=0.025), respectively. The median cost per expected success was $6568 for gemifloxacin and $7321 for ceftriaxone (P=0.29). Oral gemifloxacin is clinically effective and has an economic advantage over ceftriaxone, followed by oral cefuroxime with or without a macrolide.