The objective of this study was to assess the genetic diversity of the Sirohi goat for DRB and DQB1 loci, and to study their association with antibody response induced by the Peste des petits ruminants (PPR) vaccine. A total of 360 Sirohi kids were studied using single stranded confirmation polymorphism (SSCP) followed by polymerase chain reaction sequence-based typing (PCR-SBT) for DRB and DQB1 diversities. The competitive enzyme-linked immuno-sorbent assay (C-ELISA) was used to evaluate immune response post-PPR vaccination. Study revealed rich diversity of major histocompatibility complex (MHC) region in goat. A total of 18 DRB and 15 DQB1 alleles were obtained which were new. Alleles DRB*0104 and DQB1*0101 were the most common. The approach of SSCP combined with PCR-SBT reflects cost-effective and most powerful approach to decipher the genetic diversity in complex MHC region. Study revealed variation in DRB and DQB1 genes in Sirohi flock along with high Wu–Kabat index. A totalof 16 of the 89 amino acid residue sites in DRB and 19 of 86 residue sites in DQB1 had more than three amino acid substitutions. Positive evolutionary selection was evident in Sirohi forMHC region. Nonsignificant association of DRB and DQB1 genotypes with PPR virus (PPRV) vaccine response revealed complexity of the phenotype and importance of other factors for vaccine response. Rich diversity of DRB and DQB1 genes reflects the fitness of the population and importance of this locus for future selection programmes.