Aim: To analyze the distribution of CYP2D6 variants in two ethnically-related Mexican Native and Mestizo populations cohabitating the same econiche and their relationships with a distant Mestizo community. Materials & methods: 314 volunteers were genotyped for CYP2D6 gene variants (*2, *3, *4, *6, *10, *13, *17, *35 and *41) using predesigned TaqMan probes. CYP2D6*5 and CYP2D6 wtxN were assessed by XL-PCR. Results: CYP2D6*1, *2, *4 and *10 variants represented above 80.9% of total alleles. Chiapanecan communities showed low allele diversity compared with the northeastern population. Principal component analyses demonstrated clustering of both Mestizo populations. Variants associated to ultrarapid and poor metabolism were rare in Natives. Conclusion: Sharing of CYP2D6 alleles in both Chiapanecan populations suggests an ongoing gene-flow. Original submitted 8 December 2014; Revision submitted 13 February 2015