Humans appear to have spread to several parts of the Indian subcontinent by the middle Paleolithic period. It also provided a major passage for the distribution of modern humans. For the first time generic human leucocyte antigen (HLA) class II (DRB1) genotyping was performed using polymerase chain reaction–sequence-specific primer (PCR-SSP) (low-resolution) technique in two endogamous groups (Hindu-Brahmins and Sunni-Muslims) from the southern state of Andhra Pradesh in order to decipher the genetic affinity between them and with other populations. Calculation of genetic distances, construction of neighbour-joining dendograms and principal-component (P-C) maps were executed using HLA allelic frequencies. The present study reveals the genetic affinity of the Brahmin and Muslim populations from the state of Andhra Pradesh. The dendograms demonstrated that Indian populations form a separate cluster with oriental populations on one side and the eastern and the western Mediterranean populations on the other side. The principal component maps showed the clustering of Indian populations in the lower-right quadrant, where in the Sunni-Muslims occupied a position more closely to the north Indian Brahmins and the Bhargavas than to the geographically related south Hindu-Brahmin group. The study hypothesizes that unlike Brahmins who can be considered as an immediate stock of the Caucasians, the ancestors of Muslims might have been the result of an admixture between the Indo-Europeans and proto-Dravidians.