Human leukocyte antigen (HLA)-E is a nonclassical class I (Ib) gene with a restricted polymorphism. Only eight DNA alleles and three proteins of this gene have been described and their frequencies analyzed in Caucasian, Oriental, Asian Indian, and Negroid populations. In the present study, HLA-E polymorphism has been analyzed in six Amerindian and Mestizo populations from North and South America and compared with previously described populations. HLA-E*0101 is the most frequent allele found in all populations except in Afrocolombian and Wayu Amerindians, in which blood group analyses show a high admixture with Caucasian and African populations. Mazatecan and Mapuche (two Amerindian groups from North and South America, respectively) presented similar HLA-E frequencies, whereas Wayu Indians are more similar to the Afrocolombian population. The Mexican and Colombian Mestizo show similar allele frequencies to Amerindians with high frequencies of HLA-E*0101 and HLA-E*010302 alleles. Also, frequencies in Negroids and Asian Indians present a similar distribution of HLA-E alleles. These data are in agreement with worldwide restricted polymorphism of HLA-E because no new allele was detected in the six populations studied. The allelic frequencies show differences among Caucasian, Oriental, Mestizo and Indian populations. Ape major histocompatibility complex-E allelism is also very restricted: common chimpanzee (one allele); bonobo (two alleles); gorilla (two alleles); orangutan (one allele); rhesus monkey (eight alleles); cynomolgus monkey (two alleles); and green monkey (two alleles).