Gram-negative bacteria such as Klebsiella pneumoniae and Escherichia coli are the most common cause of pyogenic liver abscess (PLA). We investigated whether the use of anaerobic-covering antibiotics is essential for the treatment of pyogenic liver abscess.We analyzed the Health Insurance Review and Assessment Service data in Korea between 2007 and 2017. We classified PLA into two groups: a group using antibiotics that inhibited only aerobic strains (anaerobe (-) group) and a group using antibiotics that inhibited both aerobic and anaerobic strains (anaerobe (+) group). The primary outcome was the difference in in-hospital mortality between the two groups.During this period, a total of 30,690 PLA patients were obtained. There were 6733 patients in the anaerobe (-) group and 23,957 patients in the anaerobe (+) group. In-hospital mortality was significantly lower in the anaerobe (+) group than the anaerobe (-) group (7.9% vs. 15.6%, p < 0.001). In multivariate analysis, the use of anaerobic antibiotics reduced the in-hospital mortality by 42% (odds ratio 0.42, 95% confidence interval 0.38-0.46, p < 0.001) after adjusting for age and comorbidities. Furthermore, the improvement of in-hospital mortality was present regardless of the presence of cancer or diabetes.The use of broad-spectrum empirical antibiotics covering anaerobic strains is important for the treatment of pyogenic liver abscess.