PURPOSE: This study was conducted in order to determine the most cost-effective strategy, in terms of interval and age range, for liver cancer screening in the high-risk population of Korea. MATERIALS AND METHODS: A stochastic model was used to simulate the cost-effectiveness of liver cancer screening by combined ultrasonography and alpha-fetoprotein testing when varying both screening intervals and age ranges. The effectiveness of these screening strategies in the high-risk population was defined as the probability of detecting preclinical liver cancer, and cost was based on the direct cost of the screening and confirmative tests. Optimal cost-effectiveness was determined using the incremental cost-effectiveness ratio. RESULTS: Among the 36 alternative strategies, one-year or two-year interval screening for men aged between 50 and 80 years, six-month or one-year interval screening for men aged between 40 and 80 years, and six-month interval screening for men aged between 30 and 80 years were identified as non-dominated strategies. For women, identified non-dominated strategies were: one-year interval screening between age 50 and 65 years, one-year or six-month interval screening between age 50 and 80 years, six-month interval screening between age 40 and 80 years, and six-month interval screening between age 30 and 80 years. CONCLUSION: In Korea, a one-year screening interval for men aged 50 to 80 years would be marginally cost-effective. Further studies should be conducted in order to evaluate effectiveness of liver cancer screening, and compare the cost effectiveness of different liver cancer screening programs with a final outcome indicator such as quality-adjusted life-years or disability-adjusted life-years.