Aim: In previous CYP2D6 genotyping studies in Mexican–Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. Materials & methods: In the present study we evaluated the hypothesis of low frequency of PMs in Mexican–Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. Results: The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. Conclusion: The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican–Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations. Original submitted 16 May 2014; Revision submitted 26 September 2014