The Japanese Respiratory Society has recently formulated practice guidelines for the management of adult patients with community-acquired pneumonia. The guidelines recommend the use of various oral antibiotics at individual physicians' discretion. We compared the cost-effectiveness of amoxicillin/clavulanate (AMPC/CVA), azithromycin (AZM), clarithromycin (CAM), cefdinir (CFDN), levofloxacin (LVFX), and minocycline (MINO), when used on an ambulatory basis. We performed a formal cost-effectiveness analysis from the perspective of direct cost payers in the framework of the Japanese medical system. Outcomes considered were quality-adjusted life days (QALD), costs per patient, and incremental costs per quality-adjusted life year (QALY) gained. Under baseline conditions, the effectiveness of MINO, AZM, CAM, and LVFX were on a par and higher than that of AMPC/CVA or CFDN by 125-290.5 QALD. The least expensive antibiotic was MINO (55,070 to 59,208 yen), followed by AZM (56,049 to 60,188 yen), CAM (56,171 to 60,309 yen), LVFX (61,988 to 66,127 yen). AMPC/CVA (122,432 to 133,797 yen), and CFDN (123,375 to 134,649 yen). Thus, MINO, AZM, and CAM were cost-effective antibiotics for adults with community-acquired pneumonia. Sensitivity analyses revealed that the initial success rate of each antibiotic was crucial in determining cost-effectiveness. When the number of times antibiotics are taken in a day and the period of therapy were taken into account, AZM was most beneficial with 917,179-1,152,694 yen (US$ 7,643-9,606) per additional QALY over MINO in patients without comorbidity. This result, however, was not applicable to patients with chronic lung disease. MINO was the least expensive and the most cost-effective in empirically treating adult patients with community-acquired pneumonia on an ambulatory basis. AZM provides a higher quality of life for adults without comorbidity with generally acceptable marginal cost.