The long-term evolution of major histocompatibility complex (MHC) involves the birth-and-death process and independent divergence of loci during episodes punctuated by natural selection. Here, we investigated the molecular signatures of natural selection at exon-2 of MHC class II DRB gene which includes a part of the peptide-binding region (PBR) in seven of eight putative extant Felidae lineages. The DRB alleles in felids can be mainly divided into five lineages. Signatures of trans-species polymorphism among major allelic lineages indicate that balancing selection has maintained the MHC polymorphism for a long evolutionary time. Analysis based on maximum likelihood models of codon substitution revealed overall purifying selection acting on the feline DRB. Sites that have undergone positive selection and those that are under divergent selective pressure among lineages were detected and found to fall within the putative PBR. This study increased our understanding of the nature of selective forces acting on DRB during feline radiation.