The HLA allele frequency distribution of the Mexican Mazatecan Indians (Olmec culture) has been studied and compared with those of other First American Natives and worldwide populations (a total of 12,100 chromosomes; 6,050 individuals from 59 different populations). The main conclusions are: 1) An indirect evidence of Olmec and Mayan relatedness is suggested, further supporting the notion that Olmecs may have been the precursors of Mayans; 2) Language and genetics do not completely correlate in microenvironmental studies; and 3) Peopling of the Americas was probably more complex than postulated by Greenberg and others (three peopling waves). Significant genetic input from outside is not noticed in Meso and South American Amerindians according to the phylogenetic analyses; while all world populations (including Africans, Europeans, Asians, Australians, Polynesians, North American Na-Dene Indians and Eskimos) are genetically related. Meso and South American Amerindians tend to remain isolated in the Neighbor-Joining, correspondence and plane genetic distance analyses.