Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with most cases arising in patients with cirrhosis or chronic hepatitis B. Current guidelines recommend semi-annual ultrasound with or without alpha-fetoprotein (AFP) testing for all at-risk individuals; however, this one-size-fits-all approach has important limitations, including suboptimal sensitivity, frequent false-positive results, poor adherence, and failure to account for substantial heterogeneity in individual HCC risk. This evidence concerns the gene AFP and chronic hepatitis B virus infection.