Background Thiopurines are effectively prescribed for immune and oncology diseases but their toxicity leads to severe myelosuppression. Therefore, TPMT genetic variants have been used to adjust dosing for poor and intermediate metabolizers, significantly preventing adverse drug reactions. In 2018, the Clinical Pharmacogenetics Implementation Consortium included NUDT15 rs116855232 to also guide thiopurines dosing. This variant is not present in Caucasians but have been identified in 10% of Asian and Latin American populations. Despite research efforts to portrait the world's genetic variation, few studies include the investigation of NUDT15 in large samples. Methods Fifteen NUDT15 and TPMT variants were retrieved for 1270 Mestizos and 20 Natives genotyped from previous studies using the GSA-Illumina microarray. After bioinformatic quality controls, genotypes were available for 12 variants, TPMT rs2842949, rs2842950, rs2842934, rs1800460, rs12201199, rs12663332, rs2518463, rs4449636, rs12529220, rs3931660, rs200591577, and NUD15 rs116855232. Allele frequencies and haplotypes were assessed using PLINK, R, and Haploview. Dosing inferences were described according to the Clinical Pharmacogenomics Implementation Consortium. Results We report relevant populations differences in actionable TPMT*3B and NUDT15 rs116855232 as the allele frequency of the former is higher in Mestizos compared to Caucasians, and for the latter we report twofold and 1.35-fold higher allele frequencies in Natives and Mestizos compared to Mexicans from Los Angeles. Conclusions TPMT*3B and NUDT15 rs116855232 actionable markers showed population differences that ought to be considered as dosing inferences highlight the relevance of routine genotyping of these variants for the prescription of thiopurines in Mexican populations.