Cyclooxygenase (rlCOX) is a key enzyme in the synthesis of prostanoids. Two isoforms of this enzyme have been identified: COX‐1 and COX‐2. Recent studies have suggested that COX‐2, but not COX‐1, may play a role in colorectal tumorigenesis. In the present study, we investigated the expression of COX‐2 as well as COX‐1 in human hepatocellular carcinoma (HCC) tissues using immunohistochemistry and immunoblotting. Forty‐four surgically resected HCC tissues with adjacent nontumorous livers (NTs), involving 17 cases of chronic viral hepatitis and 27 cases of cirrhosis, and 7 surgically resected, histologically normal liver tissues were used. The well‐differentiated HCC expressed COX‐2 more frequently and strongly than less‐differentiated HCC or hepatocytes of NTs. Less‐differentiated HCCs expressed less COX‐2 than hepatocytes of NTs, which showed scattered, strong COX‐2 expression. Histologically normal liver was weakly positive for COX‐2. The expression of COX‐1 was weaker than that of COX‐2 in hepatic neoplastic and non‐neoplastic parenchymal cells. An enhanced expression of COX‐1 was not observed in well‐differentiated HCCs. Immunoblotting also confirmed up‐regulation of COX‐2, but not COX‐1, in well‐differentiated HCCs. The present study is the first to demonstrate a high expression of COX‐2 in well‐differentiated HCC and a low expression in advanced HCC, in contrast to its continuous expression during colorectal carcinogenesis. These findings suggested that COX‐2 may play a role in the early stages of hepatocarcinogenesis, but not in the advanced stages, and may consequently be related to HCC dedifferentiation.