Although cefepime and piperacillin/tazobactam are commonly prescribed for the treatment of hospital-acquired pneumonia (HAP), which one is the superior therapy remains unclear. Using Korean National Health Insurance Service data from January 2018 to December 2018, we compared the clinical outcomes of patients with HAP who were treated with cefepime and those treated with piperacillin/tazobactam. Data from 9955 adult patients with HAP, of whom 1502 (15%) received cefepime and 8453 (85%) received piperacillin/tazobactam, were retrieved for primary analysis. Tube feeding, suctioning, positioning care, and intensive care unit admission were more common among patients who received piperacillin/tazobactam. Treatment outcomes, including rates of in-hospital mortality, pneumonia-related readmission, and all-cause mortality within 6 months after discharge, were comparable between the two groups. In a subgroup analysis of data from patients who required tube feeding, the risk for in-hospital mortality was significantly higher among those who received cefepime (fully adjusted odds ratio, 1.43; 95% confidence interval, 1.04–1.97;p= 0.042). Treatment outcomes did not differ between patients who received cefepime and those who received piperacillin/tazobactam treatment, but among patients who were at risk for aspiration, such as those receiving tube feeding, those who received piperacillin/tazobactam had lower rates of in-hospital mortality.