The global incidence of pyogenic liver abscess (PLA) is increasing, but related reports of malignant tumor-related PLA are infrequent. Potential malignant tumors of PLA have been reported, but there is no relevant predictive model for this subsection of patients.To explore the risk factors of malignant tumor-related PLA.A retrospective analysis about a total of 881 patients who had been diagnosed with PLA from January 2005 to May 2018 was performed. The incidence of malignant tumor-related PLA in the study was 9.99% (88/881) out of all PLA cases. And that of potential malignant tumors with PLA was 4.65% (41/881). There were 62 patients with malignant tumor-related PLA in the observation group, while 146 cases without malignant tumor-related PLA were considered as control group. The data from 52 cases of malignant tumor and nonmalignant tumor-related PLA was verified.The malignant tumor type was mainly hepatobiliary malignant tumor, which occupies 72.3% (45/62) in all malignant tumor related PLA cases used to the model. Compared with nonmalignant tumor group, the rate of ineffective and mortality was higher in the malignant tumor group [19.4%(12/62) vs 7.5%(11/148), P = .01]. Multivariate analysis suggested that hepatobiliary interventional therapy or surgery, hepatitis B virus infection, multiple abscesses, portal embolism, and bile duct dilatation were independent risk factors for potential malignant tumors within the patients who combined with PLA.PLA could be considered as an early warning sign of potential malignant tumors. Malignant tumor-related PLA had a poor prognosis. Patients with PLA who have more than one independent risk factor or logit(P) > -1.694 may be considered as the high risk group for potential hepatobiliary or colorectal malignant tumors.