This study examined clinico-histopathologic differences between North American patients who developed hepatocellular carcinoma with and without cirrhosis. Histologic slides and clinical records of cases were reviewed. Cases were classified according to defined histopathologic criteria. Analyses were performed using appropriate tests. A total of 42.6% of cases were noncirrhotic. The trabecular type of hepatocellular carcinoma was the most common growth pattern in both groups. Patients with cirrhosis were significantly older, had high grade tumors, and local portal venous invasion significantly more often than patients without cirrhosis. Encapsulated tumors occurred in significantly more in patients without cirrhosis. Patients without cirrhosis survived longer than patients with cirrhosis (P < .0001) and had a better 5-year survival experience. On average, in patients with cirrhosis, serum aspartate transaminase and total serum bilirubin were significantly greater, and serum albumin was significantly lower. In general, hepatocellular carcinoma in North American patients with cirrhosis tended to be less well differentiated than those found among patients without cirrhosis. The pathology, natural history, and prognosis of this tumor is significantly influenced by the presence or absence of cirrhosis in the nonneoplastic liver, and the presence of cirrhosis portends a poorer prognosis.