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Background Portal vein tumor thrombosis (PVTT) is a common complication of hepatocellular carcinoma (HCC). The presence of PVTT (HCC-PVTT) at diagnosis often signifies advanced liver cancer, worsened liver function, increased risk of intrahepatic dissemination, systemic metastasis, and complications related to portal hypertension. Currently, the diagnosis of PVTT primarily depends on imaging techniques, with a notable lack of simple and cost-effective diagnostic markers to complement and enhance the prediction of PVTT occurrence. Objective To investigate the impact of serum high-density lipoprotein-cholesterol (HDL-C) levels on the development of PVTT in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), and explore the predictive value of HDL-C levels for PVTT occurrence. Methods A total of 119 patients diagnosed with NBNC-HCC admitted to the Third Hospital of Hebei Medical University from January 2015 to December 2020 (including 26 patients with PVTT) were selected, and 102 patients with HBV and HCV-associated hepatocellular carcinoma (BC-HCC) hospitalized during the same period (including 34 patients with PVTT) were selected. Baseline data were collected through the electronic inpatient record system, and patients with NBNC-HCC were followed up until December 31, 2022 to record their overall survival. Patients with PVTT in NBNC-HCC and BC-HCC were categorized into the NBNC-PVTT group (n=26) and BC-PVTT group (n=34), respectively, and their baseline characteristics were compared. Additionally, NBNC-HCC patients were divided into the PVTT group (n=26) and the non-PVTT group (n=93) based on the presence or absence of PVTT, and comparisons were made regarding clinical baseline characteristics and survival outcomes between the two groups. Multivariate Logistic regression analysis was performed to identify independent factors influencing PVTT in NBNC-HCC. The predictive performance of HDL-C levels for PVTT in NBNC-HCC was evaluated using receiver operating characteristic (ROC) curves. Kaplan-Meier survival curves were plotted to assess the prognosis of NBNC-HCC patients at different HDL-C levels. Furthermore, restricted cubic spline plots were utilized to analyze the nonlinear relationship between HDL-C levels and the risk of mortality in NBNC-HCC patients. Results Compared to the BC-PVTT group, the NBNC-PVTT group exhibited higher levels of age, total bilirubin (TBIL), direct bilirubin (DBIL), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), while the proportion of males and the HDL-C levels were lower (P<0.05). Multivariate Logistic regression analysis revealed that serum HDL-C level was an independent factor influencing PVTT in NBNC-HCC patients (OR=0.170, 95%CI=0.054-0.533, P=0.002). ROC curve analysis showed that the area under the curve (AUC) for HDL-C in predicting PVTT in NBNC-HCC patients was 0.702 (95%CI=0.587-0.817), with sensitivity and specificity values of 84.6% and 51.6%, respectively, and an optimal cut-off value of 0.675 mmol/L. NBNC-HCC patients were divided into a low HDL-C group (≤0.675 mmol/L, n=67) and a high HDL-C group (>0.675 mmol/L, n=52). Survival curve analysis indicated that patients in the high HDL-C group had better survival outcomes than those in the low HDL-C group (χ2=27.566, P<0.000 1). After adjusting for age and sex, a nonlinear association between HDL-C levels and the risk of death in NBNC-HCC patients was observed (Pnonlinear=0.003 2). Conclusion Serum HDL-C level serves as a predictive marker for the risk of progression of PVTT in NBNC-HCC patients, it also has a significant impact on the prognosis of NBNC-PVTT patients, offering valuable insights for risk classification management and prognosis enhancement.