OBJECTIVES Italian recommendations for human papillomavirus (HPV) immunization programmes currently target females only. However, males can be vectors in virus transmission and are at risk of disease infection. The BEST II study was designed to evaluate the cost-effectiveness (CE) of different interventions targeting females as well as males, and the economic impact of vaccination on a wide range of HPV-induced diseases. METHODS A dynamic Bayesian Markov model was developed to investigate HPV transmission between sexual partners and the cost-effectiveness of several HPV vaccination strategies. Both sexes were included in a universal vaccination programme which was compared to screening-only and female-only vaccination. A range of HPV-induced diseases was considered (cervical, vaginal, vulvar, anal, head/neck and penile cancer, the associated pre-cancerous stages as well as anogenital warts). The process of sexual mixing was estimated based on age-, gender- and sexual behavioural-specific factors to estimate the force of infection dynamically. The degree of susceptibility to the virus, associated with early sexual debut, high number of partners, smoking and previous STIs, was also included. We considered several scenarios; the baseline assumes universal vaccination to be implemented for 12-year-old females and males. The follow-up period was 55 years. RESULTS According to our preliminary analysis, universal vaccination resulted as a cost-effective alternative when compared to screening-only (with an incremental CE ratio, ICER, of €1,200) and to female-only vaccination (ICER = €6,900). We performed extensive sensitivity analyses to parametric assumptions, which confirmed the good CE profile of universal vaccination in Italy. CONCLUSIONS Universal HPV vaccination of male and female cohorts is cost-effective compared to cervical screening and female-only vaccination, when accounting for a great variety of HPV-related diseases. This is mainly due to the fact that universal vaccination increases the effects of herd immunity and provides indirect protection against HPV.