OBJECTIVES: This study assesses the cost-effectiveness of universal vaccination with RV5 in a hypothetical cohort of 1,091,156 children in Japan during their first 5 years of life. METHODS: A Markov model was developed to evaluate the cost per quality-adjusted-life-year (QALY) from the healthcare and societal perspectives. The base case scenario assumes 94% of the vaccinated cohort received 3 doses of RV5 orally at 2, 4, and 6 months of age with the remaining children receiving only 1 or 2 doses. In the absence of a vaccination strategy, there is annually 1 death, 78,000 hospitalizations, and 739,874 outpatient visits. The efficacy of RV5 was based on the results of the Rotavirus Efficacy and Safety Trial (REST). The three dose efficacy in REST was similar to the one obtained from clinical trials conducted in Japan.  RESULTS: Universal vaccination could reduce hospitalizations by 89% and all symptomatic episodes of rotavirus gastroenteritis by 59%. For the base case scenario, at a cost of JPY 5316 per dose and administration fee of JPY ,100 per dose, the cost per case avoided was JPY 22,704 and the cost per QALY saved was JPY 2,230,978 from the healthcare payer perspective. From the societal perspective, the cost per case avoided was JPY 8,934 and the cost per QALY saved was JPY 877,855. CONCLUSIONS: Using three times the GDP per capita as a threshold, universal vaccination with RV5 is likely to be cost-effective and to result in substantial reductions in rotavirus-related healthcare use in Japan.