Argininosuccinate lyase (ASL) is an important enzyme in the hepatic urea cycle, and catalyzes the reversible reaction of argininosuccinate to arginine and fumarate. Its expression is significantly reduced in some hepatocellular carcinomas (HCC). In this study, we aimed to investigate the correlation of reduced ASL expression and clinicopathologic features and prognosis in HCC patients. Immunohistochemistry was used to determine the expression of ASL in HCC tissues from 61 patients who had undergone hepatic tumor resection. The correlation of ASL expression in HCC with background liver status, viral status, tumor size, portal vein invasion, histopathologic differentiation, early tumor recurrence, sex, and age were assessed with the χ(2) test. Patient survival and survival differences were determined by the Kaplan-Meier method and log-rank test. Cox regression (proportional hazard model) was used for multivariate analysis of prognostic factors. Strong positive staining was found in 39/61 HCCs and normal liver tissues, and reduced ASL staining was found in 22/61 HCCs (36.1%). Patients with low ASL expression had a significantly poorer overall survival and disease-free survival (both P<0.001). Reduced ASL expression in carcinoma tissues was also significantly associated with the tumor-node-metastasis stage and early tumor recurrence, and histopathologic differentiation and portal vein invasion (P<0.05). Cox regression analysis showed that ASL is an independent prognostic marker for HCC. Therefore, reduced ASL expression may be a novel maker for poor prognosis in HCC patients.