High rates of hepatitis B virus infection and primary hepatocellular carcinoma are present among Alaskan Natives. To determine if primary hepatocellular carcinoma could be detected at an early surgically resectable stage, serological screening for elevated α-fetoprotein levels was done semiannually among Alaskan Natives infected with hepatitis B virus. During a 26-month screening period, 3,387 α-fetoprotein tests were performed on 1,394 persons. Of 126 persons with elevated levels of α-fetoprotein (>25 ng/mL), nine males were found to have primary hepatocellular carcinoma (all with α-fetoprotein levels >350 ng/mL). Six of these nine persons were asymptomatic for primary hepatocellular carcinoma and four had small tumors (<6 cm) that were surgically resected. After surgery, the α-fetoprotein levels in all four patients fell to normal and have remained normal after a follow-up of four to 20 months (median, ten months). α-Fetoprotein screening proved to be an effective approach in this population in detecting primary hepatocellular carcinoma at a potentially curable stage and should be considered in other individuals or populations infected with hepatitis B virus.