One of the alcohol-related goals in Japan's health promotion campaign called Health Japan 21 (secondary term) is to reduce the number of high-risk drinkers (20 years old or above) who consume 40g or more pure alcohol/day in men and 20g or more in women by year 2022. To achieve this goal, a further expansion of screening and brief intervention (SBI) in the medical setting is essential. In this research, realistic and cost-effective SBI scenarios in Japan were investigated based on international systematic review and clinicians' opinions from a semi-structured interview. Several SBI scenarios were built with 2 levels of intervention based on the AUDIT scores of 8-15 (brief advice) and 16-19 (brief advice and counseling, continuous intervention), and a simulation was conducted by applying different probabilities and success rates into the scenarios. Information associated with preparation and implementation of SBI at the 2 levels was also estimated and annual costs of SBI per drinker were calculated. It was found that approximately 2,390,000 and 530,000 high-risk drinkers require brief and extensive interventions, respectively. Furthermore, incremental costs per quality-adjusted life year (QALY) gained were calculated at 723,415 yen for brief intervention and 944,762 yen for extensive intervention, suggesting cost-effectiveness of SBI in Japan. Given the limited national healthcare budget and operational challenges such as time to provide SBI especially in the primary care setting in Japan, roles of healthcare providers and wider use of information technology were discussed with some suggestions. Furthermore, lighter and more frequent interventions at various levels and not only at the medical setting but also at multiple social settings (such as workplace and among family and friends) were discussed to increase the cost-effectiveness of SBI and to keep the number of high-risk drinkers who have successfully reduced their alcohol consumption.