The authors assessed the cost-effectiveness of rotavirus vaccination to develop an evidence-based national immunization program in Korea. A Markov model was constructed to compare the costs and clinical outcomes of vaccination versus no vaccination. The birth cohort of 493189 infants in 2007 was followed until the age of 5 years. Korea-specific data for epidemiological characteristics and economic burden of rotavirus diarrhea were used for the modeled estimation. Efficacy of RotaTeq® was based on a recent clinical trial. Rotavirus vaccination would prevent 181238 symptomatic cases (reduction rate = 63.2%) over 5 years after birth. From the societal perspective, at a vaccination cost of 100000 Korean won (KW; 1 US$ ≈ 1200 KW) per dose, universal vaccination would cost 375 620 KW per case averted. The breakeven price of vaccine was 56061 KW. Rotavirus vaccination would reduce the burden of the disease substantially and be a cost-effective strategy to prevent rotavirus diarrhea in Korea.