Objectives: To explore evolutionary hypotheses for the high frequencies of a substitution in the methylenetetrahydrofolate reductase (MTHFR) gene, in Mexican and Central American Indigenous populations. Materials and methods: We obtained allele frequencies for the C677T variant in the MTHFR gene and ecological information for 37 indigenous samples from Mexico and Central America. We calculated Hardy-Weinberg equilibrium and computed Fst statistics. We computed correlations between the samples' allele frequencies and ecological and geochemical variables. Results: Many of the samples have extremely high frequencies of the T allele ( q = 0.62, median = 0.66). In this region, the frequency of the T allele decreases from Southeast to Northwest and is significantly correlated with longitude, latitude, altitude, and insolation. Conclusions:The native people of Central America and Mexico evolved high frequencies of an allele which has been shown to produce deleterious clinical effects including neural tube effects, cardiovascular events, and cancer. This allele has a clinal distribution in the region, perhaps associated with solar irradiation. As (Contreras-Cubas et al., 2016) noted, the traditional diet of these populations, which is high in folate, has likely mitigated the negative effect of the allele. It is of primary importance that their rights to their homeland and traditional diets be respected. It is a matter of Public Health to investigate whether this allele is a factor in the current wave of cardiovascular diseases affecting the majority population of this region, since it descends from the Native peoples and the Mediterranean population, which also has high frequencies of the allele.