Objectives: Rotavirus (RV) is the most common etiological agent of gastroenteritis in children. The oral vaccine Rix4414 was recently commercialized in Italy for prevention of RV infections. The health outcomes and the economic impact of a national RV immunization program were assessed.Design: A Markov model simulated the flow of a birth cohort on RV disease burden and costs up to age 5, comparing a RV vaccination programme with no vaccination. Lifetime cost-effectiveness for the national healthcare system (NHS) and the society (S) with a benchmark of 50,000 €/QALY was analysed.Main results: Disease’s medical direct costs exceeded 30 million €/year, while indirect costs approached 112 million €/year. A routine, universal RV immunization program, for a birth cohort of 550,000 children, would prevent 80% of RV diarrhoea, 97% of severe RV cases, 87% of medical consultations and 98% of hospitalizations. In the NHS perspective, the incremental cost/QALY would be € 14,829 and it would decrease to € −17,030 (cost-saving) in the S perspective. In the private market scenario, the incremental cost/QALY (€ 24,687) would remain far below the threshold.Conclusion: A national immunization program with Rix44141 in Italy would be cost-effective both from the S and the NHS perspective.