OBJECTIVES Human papillomavirus (HPV) infection had been demonstrated as a major risk factor for cervical cancer. Vaccines against HPV-16 and HPV-18 appeared highly efficacious in preventing HPV-16 and HPV-18 infections and cervical lesions including cervical cancer. However, only limited available data described the health and economic implications of HPV vaccination in Taiwan. The objective of this study was to assess the cost-effectiveness of prophylactic HPV vaccination for prevention of cervical cancer in Taiwan. METHODS We developed a Markov model to compare the health and economic outcomes of vaccinating preadolescent girls (at age of 12 years old) for prevention of cervical cancer with current practice. Data were synthesized from published papers, and whenever possible, those specific to Taiwan were used. The economic analysis adopted the healthcare payer's perspective, and only direct medical costs were taken into account. Sensitivity analyses were performed to account for important uncertainties and different vaccination scenario. RESULTS Under the assumption that the HPV vaccine would provide lifelong protection, vaccination among preadolescent girls in Taiwan would result in a life expectancy gain of 16.8 days or 21.2 quality-adjusted life days at a cost of US$287 as compared with the current screening practice. The incremental cost-effectiveness ratio (ICER) was US$6,236 per life year gained or US$4,946 per QALY gained given the discount rate of 3%. Sensitivity analyses showed that this ICER would remain far below US$30,000 per QALY even when vaccine compliance was unsatisfactory or vaccine-induced immunity wanned that needed booster shot. CONCLUSIONS Although gains in life expectancy may be modest at individual level, the results indicate that prophylactic HPV vaccination on preadolescent girls in Taiwan would result in substantial population benefits, i.e., it is a very cost-effective strategy in public health.