OBJECTIVES: In clinical studies, prophylactic HPV vaccines have demonstrated high efficacy in the prevention of HPV infections, cervical intraepithelial neoplasia (CIN) and genital warts. In Germany, routine HPV vaccination is recommended for females aged 12 to 17 years. No transmission model reflecting the German health-care setting which evaluates the cost-effectiveness of both the bivalent and quadrivalent HPV vaccines has been published yet. Hence, the objective of this study was to determine the long-term impact of both available vaccines in addition to the existing cervical cancer screening programme in Germany. METHODS: A mathematical model simulating the transmission dynamics and the natural history of HPV infection was developed. The age-structured model takes account of the occurrence of CIN, cervical cancer and genital warts and was calibrated using German data on HPV prevalence and cancer statistics. Epidemiological and economic parameter estimates were obtained from published literature and supplemented by expert interviews. The base-case analysis was conducted from a third-party payer perspective and assumed a vaccination coverage of 50%, 10 years of sustained vaccine protection followed by a period of waning immunity, costs of €474 for the initial immunisation series and a 3% discount rate on future costs and health effects. RESULTS: Compared with current screening practice, vaccination of 12-year-old girls prevented additional 97,822 cervical cancer cases and 23,462 deaths over a time horizon of 100 years. Under base-case assumptions, the discounted ICERs were €57,413 per life-year gained and €37,198 per QALY gained for the bivalent vaccine, and €36,700 per life-year gained and €15,229 per QALY gained for the quadrivalent vaccine. CONCLUSIONS: Considering the commonly accepted threshold of €50,000 per QALY gained, routine HPV-vaccination of 12-year-old girls is likely to be cost-effective in Germany. Additional protection against genital warts in females and males by the quadrivalent vaccine improves the cost-effectiveness ratio substantially.