OBJECTIVES: Hepatocellular carcinoma (HCC) is the fifth cause of dead from cancer worldwide. Hepatitis B virus infection is the important risk of HCC. Alpha fetoprotein (AFP) and liver ultrasound had been introduced as semi-annual screening test for HCC in human with hepatitis B surface antigen positive or patients with chronic hepatitis B. However, the cost-effectiveness of this screening is not well defined. Our objective was to explore the cost-effectiveness of semi-annual HCC screening using AFP and liver ultrasound from societal perspective compared with no screening. METHODS: With a Markov model, we simulated the four health states of natural history of HCC which were no HCC state, resectable HCC state, unresectable HCC state and death state with 6-month cycle lenght. The based case decision model was run for male patients with age of 51 that is mean age of screening group. Cost and outcomes were discounted at a 3% annual rate. Probabilistic sensitivity analysis was performed. RESULTS: For semi-annual HCC screening, the incremental cost effectiveness ratio (ICER) which compared with no screening was US$14,111 (95%CI US$13,650-US$14,573) per quality adjusted life year (QALY) for male chronic HBV patients. CONCLUSIONS: AFP with liver ultrasound is not cost effective for semi-annual screening HCC in patients with hepatitis B surface antigen positive or patients with chronic hepatitis B, according to the Thai threshold that ICER of cost-effective intervention should not be exceed US$ 9000 per QALY.