Apolipoprotein E (APOE) genotypes were determined in 75 Mazatecan Indians and 83 Mexican mestizos. APOE allele and genotype frequencies in Mazatecans and mestizos were similar, with high frequencies of the APOE*3 allele (0.900 and 0.915, respectively) and the E3/3 genotype (0.813 and 0.831, respectively) and an absence in both samples of the APOE*2 allele. Our data are similar to those previously described for Mexican-American and Mayan populations, which show the highest frequency worldwide of the APOE*3 allele and the E3/3 genotype. Mazatecans and mestizos also show a decreased frequency of the APOE*4 allele when compared to other Amerindian groups. The absence of the APOE*2 allele has also been reported in other Amerindian groups such as Mayans and Cayapa, whereas in Caucasians the average frequency of this allele is about 8%. Our data are in agreement with previous reports showing absence of the APOE*2 allele in Native American groups. These findings suggest that the APOE*2 allele was absent in humans from northern Asia who settled in the Arctic and populated the American continent.