INTRODUCTION: Conditional economic incentives can improve medication-taking behaviors among populations at risk of contracting human immunodeficiency virus (HIV). However, there are no data on the cost-effectiveness of incentive programs for improving pre-exposure prophylaxis (PrEP) adherence among male sex workers (MSWs) who have one of the highest HIV acquisition rates. Our objective was to assess the cost-effectiveness of incentive programs to improve adherence to pre-exposure prophylaxis (PrEP) among male sex workers METHODS: We conducted an economic evaluation of the PrEP Seguro randomized pilot trial in Mexico (ClinicalTrials.gov: NCT03674983). Among n = 110 MSWs, those randomized to the intervention received tiered incentives based on PrEP drug levels in scalp hair measured at three clinic visits over 6 months. The intervention led to a 28.7% increase in scalp hair PrEP concentration, consistent with increased adherence (p = 0.05). Here we use a micro-costing approach from the health system perspective to calculate costs. Quality-adjusted life years (QALYs) were estimated from the number of HIV infections averted through sufficient PrEP adherence (tenofovir concentration > 0.011 ng/mg corresponding to greater than or equal to three weekly doses). Incremental cost-effectiveness ratios (ICERs) estimated the cost/QALY gained owing to the intervention. RESULTS: The mean cost per patient was US $165.53 and $179.55 among standard care and incentive patients, respectively. Over 6 months of follow-up, 62% of standard care patients and 78% of incentive recipients were PrEP adherent. After the program, the lifetime average QALYs gained per infection avoided were 9.17 (minimum, maximum: 7.5, 10.8) and 9.84 (minimum, maximum: 8.05, 11.6) among standard care and incentive patients, respectively. The 6-month ICER was US $20.92/QALY gained by the intervention, which was highly cost-effective at a willingness-to-pay of US $8655 (Mexico's 2020 per capita gross domestic product (GDP)). DISCUSSION: Using behavioral economics approaches for enhancing adherence to HIV prevention may offer health and fiscal benefits through reduced HIV incidence. Fully powered implementation trials can determine future cost-effectiveness of scaling up incentives for PrEP adherence among high-risk populations.