OBJECTIVES: To estimate the cost-effectiveness of mass-vaccination with an oral rotavirus vaccine (RIX4414) compared to no vaccination from a societal perspective. METHODS: A Markov model was constructed for a hypothetical birth cohort, comparing two treatment arms, one receiving the vaccine, the other receiving standard care. In the model, seasonality of the virus, protection from breastfeeding, and nosocomial infections are taken into account. Direct medical costs and costs due to loss of productivity (of the parents) were estimated. Effects were expressed as the number of hospitalisations, GP visits, deaths, nosocomial infections, and the quality adjusted life years (QALYs) over a lifetime horizon. Costs and QALYs were combined into an incremental cost-effectiveness ratio (ICER). Data for the model were obtained from published local data on incidence of rotavirus infection and consequential health care consumption and from clinical studies measuring the effectiveness of the vaccine. Costs and effects were discounted at 4% and 1.5%, respectively. A probabilistic sensitivity analysis was performed. RESULTS: Mass-vaccination with RIX4414 shows a reduction in the number of GP consultations by 95.8%. Hospitalisations, nosocomial infections and deaths were reduced with 100%. This results in savings of €9.2 million for direct medical costs and of €3.4 million for productivity costs, whereas the costs of vaccination amount to €16.5 million. Furthermore, 0.002 QALYs are gained, yielding an ICER of €10,245. Sensitivity analysis shows that the probability for nosocomial infection and the probability of hospitalisation have the largest effect on the outcome. However, the prioritisation of the alternatives does not alter. CONCLUSIONS: The resulting ICER is comparable to that of pneumococcal vaccination of infants (€10,300 per QALY gained), which was recently added to the Dutch immunisation program. Therefore, mass vaccination against rotavirus disease with RIX4414 appears to be cost-effective and economically attractive from a societal perspective.