BACKGROUND: The increasing incidence of hepatocellular carcinoma coupled with this cancer’s high mortality is a public health problem. Delineating high-risk populations and cancer patterns can provide valuable information. This is necessary to broaden screening and surveillance guidelines related to early detection and prevention. METHODS: By using data collected by the Surveillance, Epidemiology, and End Results program, a population-based cancer registry in the United States, our retrospective cohort study evaluated sex-specific, race/ethnicity-specific, and age-specific variations in hepatocellular carcinoma incidence from 1992 to 2004. RESULTS: With men and women combined, the incidence of hepatocellular carcinoma among Asians was the highest, nearly double that of white Hispanics (11.0 vs 6.8 per 100,000/y), and more than 4 times higher than that of Caucasians (11.0 vs 2.6 per 100,000/y). Although male subjects demonstrated a doubling of cancer rates every 10 years from 30 to 50 years of age, female subjects reached male-comparable rates of cancer 10 to 15 years later and peaked at significantly lower values for all race and ethnic groups. CONCLUSION: Marked differences in the incidence rates of hepatocellular carcinoma by sex, ethnicity, and age of diagnosis likely represent variations in risk factor distributions (eg, viral hepatitis) and possibly in host genetics or other environmental factors. An individualized approach tailored to specific risk profiles may more effectively identify treatable tumors than more general guidelines.