Host immune response against Mycobacterium leprae plays an important role in providing resistance to infection and disease progression. Genome-wide linkage and association studies suggest the possibility of multiple risk loci within HLA (6p21.3) region. Any systematic study of relevance within the histocompatibility complex of importance in host immune response would be pertinent because of non-replication of the known loci and unavailable information on some of the unexplored genes and regions. A systematic scan was performed of the selected region involving LTA-TNF-LTB genes within 6p21.3 with a resolution of 1SNP/127 bp; and the SNPs in flanking BAT1, NFKBIL and BTNL2-DRA genes on the basis of their tag status or their presence in promoter/exonic regions with MAF of >5%. Nine SNPs located in BAT1, LTA, TNF genes and BTNL2-DRA interval showed strong association with leprosy susceptibility in two independent sets of North Indian population which was replicated in a geographically distinct East Indian population. Conditional logistic regression showed at least one functional SNP remaining significant in each gene, suggesting an independent role of each of the disease associated SNPs. In vitro reporter assay revealed that two SNPs located at BAT1 promoter and 13 kb upstream to LTA gene affected the transcription factor binding site, hence the gene expression. We unravel the role of unexplored immunologically important genes, BAT1 and BTNL2, in addition to known LTA and TNF genes, and the haplotypes of the significantly associated SNPs therein, to understand susceptibility to the disease, leprosy and its differential severity.