Hepatocellular carcinoma (HCC) is a growing health problem worldwide. The limited treatment and poor prognosis of this disease emphasizes the importance of developing effective prevention, including chemoprevention. Improvement in early diagnosis of HCC and regular screen of individuals with increased risk for HCC provide the possibility of effective chemoprevention for HCC in the future. Hepatocarcinogenesis is best described as a continuity of regeneration, proliferation, unregulated hyperplasia, dysplasia, and malignant transformation. Uncontrolled proliferation of hepatocytes clearly plays a key role in hepatocarcinogenesis. Overexpression of cyclooxygenase-2 (COX-2) has been associated with tumorigenesis of colon cancer. Selective COX-2 inhibitors possess potent suppression on the growth of colon cancer. Overexpression of COX-2 has also recently been demonstrated in patients with HCC, especially in nontumorous tissue with cirrhosis and well-differentiated tumorous tissue. In vitro studies have revealed that both NS-398, a selective COX-2 inhibitor, and sulindac, an analog of nonsteroidal anti-inflammatory drugs, effectively inhibit growth of human hepatoma cell lines, which is mediated by a decreased rate of cell proliferation. Although further in vivo studies are required in animal models to confirm these findings and define optimal doses for future clinical trials in human subjects, these findings provide a rationale for the use of COX-2 inhibitors as HCC chemoprevention.