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Abstract In this study, we aimed to investigate the impact of aspirin on the risk of pyogenic liver abscess caused by Klebsiella pneumoniae (KP-PLA) and invasive KP-PLA syndrome (IKPS) in diabetic patients. Diabetic patients who were propensity-score matched were retrospectively included from hospital-based database. Kaplan–Meier approach with a log-rank test was used to compare the cumulative incidences of KP-PLA including IKPS between aspirin users and non-users. Totally, 63,500 patients were analyzed after propensity-score matching (1:1). Compared with that of non-users, the incidence of KP-PLA was significantly reduced in aspirin users (0.31% vs. 0.50%, p < 0.01), but not for that of IKPS (0.02% vs. 0.03%, p = 0.29). Patients taking aspirin for ≥ 90 days had a significantly lower risk for KP-PLA (hazard ratio, 0.67; 95%CI, 0.50–0.90). Females, taking clopidogrel or metformin for ≥ 90 days, and taking H2-blockers or proton pump inhibitors (PPIs) for ≥ 5 days were also associated with a lower risk of KP-PLA. However, cholangitis and a glycated hemoglobin ≥ 8.5% were associated with an increased risk of KP-PLA.