Pneumonia is an acute infection that affects lung tissue. The disease affects all age groups. Pneumonia is classified into three categories: community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Antibiotics are used to treat pneumonia. Given the wide range of antibiotic options, an analysis is needed to determine which antibiotics are most effective. This study aims to determine which antibiotic Levofloxacin or Ampicillin-Sulbactam plus Azithromycin is the most cost-effective for the treatment of pneumonia among inpatients at Dr. Moewardi General Hospital in Surakarta from January through December 2025. This was a descriptive observational study with retrospective data collection. A total of 100 patients were selected using purposive sampling; these were inpatients with pneumonia aged ≥ 18 years who had complete medical records and therapy cost data. This study used the Cost-Effectiveness Analysis (CEA) method from two perspectives the hospital’s and the National Health Insurance Agency’s to determine the degree of effectiveness and the Average Cost-Effectiveness Ratio (ACER). The use of antibiotics may be considered, specifically Levofloxacin (80%) and Ampicillin-Sulbactam + Azithromycin (20%). Levofloxacin has a higher therapeutic efficacy (86.25%) compared to Ampicillin-Sulbactam + Azithromycin (65%). From the perspective of hospitals and Social Security Administration Agency, the ACER values for Levofloxacin are both lower Rp 120,509 and Rp 232,286, respectively while those for Ampicillin Sulbactam + Azithromycin are higher Rp 457,989 and Rp 628,926, respectively. Levofloxacin is more cost-effective than ampicillin-sulbactam plus azithromycin, based on its lower ACER score.