Background: Most anal cancers are caused by the human papilloma virus (HPV) infection. The incidence is increasing, especially in high-risk individuals such as HIV-positive men. Evidence shows that the new quadrivalent HPV vaccine reduces the rates of anal intraepithelial neoplasia among men who have sex with men. Objective: To determine whether vaccinating against HPV-related anal cancer is cost-effective in HIV-positive men in Chile. Methods: A cost-effectiveness analysis was conducted by constructing a cohort multistate life-table–based Markov model in MS Excel in which the prevention of HPV infection was expected to influence the incidence of anal cancer in HIV-positive men. The comparator was the current practice of no systematic HPV prevention. Estimates of the efficacy of the vaccine were obtained from a substudy of a larger randomized controlled trial, incidence rates from the Chilean Population Cancer Registries, mortality rates from the National Institute of Statistics, and disease costs from a cost-effectiveness report. A public health care sector perspective was applied. The outcome was measured in averted disability-adjusted life-years. The incremental costeffectiveness ratio was calculated considering a lifetime horizon for costs and health outcomes. Results: The estimated incremental costeffectiveness ratio was US $138,269/ disability-adjusted life-year (95% confidence interval $95,936–$221,862). Assuming a threshold of 3 times the gross domestic product per capita, the intervention was not costeffective. The outcome was sensitive to the vaccine price and vaccine efficacy. Conclusions: HPV vaccination in HIV-positive men from a Chilean public health care sector perspective is not cost-effective.