OBJECTIVES:  Recent findings show that vaccinating older men who have sex with men (MSM) with history of high-grade anal intraepithelial neoplasia (HGAIN)–a precursor to anal cancer–with quadrivalent human papillomavirus (qHPV) vaccine was associated with  50% decrease in the hazards for recurrent or persistent HGAIN. We evaluated the long-term clinical and economic outcomes of adding qHPV vaccine to the HGAIN treatment regimen HGAIN in HIV-positive MSM aged ≥ 27 years.      METHODS: Using Markov model of anal histology in HIV-positive MSM we compared two strategies–no qHPV vaccination after treatment for HGAIN versus qHPV vaccination after treatment for HGAIN. The probability of anal intraepithelial neoplasia (AIN) progression was conditional on patients’ CD4 count. Model parameters, including baseline prevalence, disease transitions, costs, and utilities were either obtained from literature or calibrated using a natural history model of anal carcinogenesis. Model output included lifetime costs, quality-adjusted life years (QALYs), and lifetime risk of developing invasive cancer. Results from the healthcare perspective were presented in the forms of incremental cost-effectiveness ratios (ICERs) and decrease in lifetime risk of anal cancer. Deterministic and probabilistic sensitivity analyses were conducted on model parameters. RESULTS:  Vaccination after treatment for HGAIN decreased the lifetime risk of anal cancer by 63% compared to the no vaccination strategy. Vaccination resulted in the decrease in lifetime costs with increase in effectiveness by 0.16 QALYs. The predicted incidence of anal cancer after vaccination was almost one-third to that of the no vaccination strategy. The results were sensitive to the model parameters–progression from HGAIN to cancer, mortality attributed to anal cancer, cost of HGAIN treatment, and discount rate.   CONCLUSIONS: Vaccinating the high-risk population of HIV-positive MSM aged ≥ 27 after treatment for HGAIN is a cost-saving strategy. Expansion of current vaccination guidelines to include this population should be a priority.