OBJECTIVES: To compare the impact of the quadrivalent (QV) (HPV 6/11/16/18) and bivalent (BV) (HPV 16/18) vaccines against HPV in Spain. METHODS: A population-based compartmental dynamic transmission model of HPV developed in the US was partially adapted to Spain updating epidemiological data of HPV related diseases, the vaccination coverage and direct costs of the diseases. The reduction of the number of cases related to HPV and savings associated with the following strategies were compared: A) cervix cancer screening (CCS) of women between 25-65 years, every 3-5 years and a vaccination program of girls between 11-26 years with the QV vaccine; B) CCS+BV vaccine. The analysis was performed from the National Health System (NHS) perspective, costs were discounted by 3% and the time horizon was 100 years. Univariate sensitivity analyses were performed to assess the uncertainty on the parameters. RESULTS: At 100 years, considering the current indications of the vaccines, lifetime protection against HPV vaccine types and 20 years of cross-protection, both strategies reduced 208 cases of vulvar and vaginal cancers and 22,796 cases of CIN2+. The strategy CCS+QV vaccine reduced 18,689 additional cases of genital warts due to the protection against 6/11 HPV types, but 4 less cases of cervix cancer and 359 less cases of CIN2+ due to better cross-protection of the BV vaccine. Nevertheless, savings accumulated during 100 years due to the reduction of genital warts cases (€215.7 million) compensated the cost associated to cervix cancers and CIN2+ that the BV vaccine additionally reduced (€3 and €27.1 million, respectively). Therefore, during 100 years the QV vaccine saves €185.4 million more than the BV vaccine. The sensitivity analyses confirmed the stability of the results. CONCLUSIONS: The QV vaccine provides higher cost savings to the NHS compared to the BV vaccine due to the additional efficacy against HPV 6/11 types.