Distinguishing hepatocellular carcinoma (HCC) from metastatic tumors is a challenging issue, especially in differential diagnosis between poorly differentiated HCC and metastasis tumors. Expression of Arg-1, HepPar-1, and α-fetoprotein (AFP) in 78 cases of HCC, 34 cases of metastatic tumors, and 228 cases of nonhepatocellular tumors of surgical specimens is measured by immunohistochemistry. Arg-1 immunoreactivity was detected in 75 of 78 (96.1 %) cases of HCC, whereas HepPar-1 and AFP immunoreactivity was detected in 63 of 78 (80.7 %) and 40 of 78 (51.3 %) cases of HCC, respectively. HepPar-1 and AFP expression was observed in three of 34 (8.8 %) cases and one of 34 (2.9 %) cases of metastatic tumors, respectively. In contrast, Arg-1 expression was absent in all 34 (0 %) cases of metastatic tumors. The sensitivity, specificity, positive predictive value, and negative predictive value of Arg-1 in distinguishing HCC from metastatic tumors and nonhepatocellular tumors are 96.1, 99.6, 98.7, and 98.8 % compared with 80.7, 92.0, 75.0, and 94.1 % for HepPar-1 and 51.3, 97.7, 87.0, and 87.1 % for AFP, respectively. Arg-1 is a more sensitive and better specific marker for HCC compared with HepPar-1 and AFP, indicating that Arg-1 can be easily applied in distinguishing HCC from metastatic tumors.