HLA-DR4 has been implicated in several diseases including rheumatoid arthritis (RA) and type I diabetes, the strength of associations being ethnically variable. Unusually high level of heterogeneity in DR4-DQB1 haplotypes has been reported in the Indian population. The present study is an attempt to determine the genetic diversity of the HLA-DR4 allelic family and its associated DQA1-DQBI haplotypic combinations in the healthy North Indian population. Using PCR-SSP and PCR-SSOP techniques, nine subtypes of DR4 were encountered of which DRB1*0403 was the most predominant allele (34.8%) followed by *0404 (27%), *0401 (14.6%), and *0405 (11%). No examples of *0402, *0409, *0411, *0413-*0417, and *0419-23 were encountered, although a few other subtypes, *0410 (three examples), *0406 and *0418 (two examples each), and *0407, *0408, and *0412 (single example each) occurred infrequently in a cohort of 85 HLA-DR4 positive samples studied. Most of these subtypes occurred in combination with DQA1*03-DQB1*0302 (69.5%). DRB1*0403 and *0404 exhibited maximum heterogeneity of DQB1 combinations. Haplotype data revealed the presence of 15 different DR4-DQ haplotypes, four of which were found to be "unique" to Asian Indians, not reported in any other population. These results help to explain the observed variability in DR4 associations in autoimmune diseases in Asian Indians and provide support for scientific and historical documentation of extensive admixture in the Indian subcontinent.