OBJECTIVES: In Mexico, efavirenz/emtricitabine/tenofovir is the standard of treatment for antiretroviral-naïve patients; however efavirenz is highly associated with neurocognitive adverse events due to its central nervous system toxicity. The aim of this analysis was to estimate the annual cost of treatment for rilpivirine/emtricitabine/tenofovir compared to available alternatives for those patients virologically suppressed and intolerant to efavirenz in Mexico. METHODS:   Nine randomized clinical trials were included to perform a meta-analysis of an unadjusted indirect comparison of alternatives evaluated in terms of the percentage of patients with undetectable viral load (HIV-RNA <50 copies/mL) at 48 weeks of treatment. A cost-minimization analysis was developed to determine the annual cost of treatment for rilpivirine/emtrcitabine/tefonovir as single tablet regimen (STR) compared to dolutegravir, raltegravir, atazanavir/ritonavir and darunavir/ritonavir as part of a highly active anti-retroviral therapy (HAART) with emtricitabine/tenofovir as backbone for patients intolerant to efavirenz in Mexican healthcare system. Cost analysis included only acquisition drug costs that were obtained from published sources. Costs are expressed in 2016 USD ($1USD=$20MXN). RESULTS:  The meta-analysis performed suggested comparable efficacy and safety between the alternatives evaluated. Annual cost of treatment for rilpivirine/emtricitabine/tenofovir was estimated in $2,458 versus $3,720 and $4,460 for dolutegravir and raltegravir schemes, respectively; and versus $3,142 and $3,475 for HAART that included atazanavir/ritonavir and darunavir/ritonavir, respectively, as third component of the regimen. Annual savings with rilpivirine/emtricitabine/tenofovir ranged from $684 to more than $2,000 per patient compared to annual cost of treatment of the other alternatives evaluated. A sensitivity analysis over the acquisition price (+/-10%) showed that even with an increase up to 10% in the cost of rilpivirine/emtricitabine/tenofovir, it remained as the least expensive alternative. CONCLUSIONS: The use of rilpivirine/emtricitabine/tenofovir as STR is a cost-saving alternative in patients intolerant to efavirenz compared to other options approved and locally available in the Mexican healthcare system.