We have evaluated health and economic benefits of a universal infant vaccination with two rotavirus vaccines registered in Italy, on the bases of the burden of rotavirus gastroenteritis (RVGE) in a birth cohort of 520,000 Italian infants followed until 5 years of age. Estimates from published and unpublished sources of disease burden, costs, vaccine coverage, efficacy trials of both vaccines, and price were used to estimate cost-effectiveness from the perspectives of the Italian National Health Service (NHS) and society. According to our estimates, a universal rotavirus vaccination program would avoid 10,679 hospitalizations, 39,202 emergency visits, and 44,223 at home visits. At 65.6 euro per vaccination courses, the program would cost 30,700,800 euro and realize a net loss of 9,057,928 euro from the Italian NHS perspective. On the contrary, the program would provide a net savings of 24,324,198 euro from the societal perspective. From the Italian NHS perspective, the break-even price per vaccination course should be reduced at least to 46.25 euro to achieve a zero cost-effectiveness ratio.