Anthropological studies based on highly polymorphic HLA genes provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as designing peptide vaccines against tumors, and infectious or autoimmune diseases.This study was designed to investigate the genetic relationship of Iranian Arabs and Jews using HLA-class II genetic diversity.HLA-DRB1, DQA1, and DQB1 allele frequencies and haplotypes were determined in 134 Iranian Arabs from two different communities and 91 Iranian Jews using PCR/RFLP and PCR/SSP methods.Neighbor-joining analyses showed a closer genetic relationship between Iranian Arabs and Iranian Jews than between either Iranian Arabs and Middle Eastern Arabs or Iranian Jews and other Jews. The results of AMOVA test also revealed no significant difference between these populations and other Iranians.It seems that, Iranian Arabs are originally from the Iranian gene pool and speak Arabic due to their encounter with Arabs. Iranian gene flow to immigrant Jews followed by their expansion in this country may also explain the close genetic relationship among different Iranian ethnic groups.