Mutations in caspase recruitment domain 15 (CARD15) are associated with susceptibility to Crohn's disease and Blau Syndrome. We performed comparative analyses of the bovine, murine, and human CARD15 transcripts to elucidate functionality of bovine CARD15 and examine its potential role in bovine disease resistance. Comparative analyses of intronic sequence across seven divergent species were performed to identify putative regulatory element binding motifs. High levels of interspecies conservation in sequence, genomic structure, and protein domains were detected indicating common functionality for CARD15 in cattle, human, and mouse. We identified species-specific regulatory elements in the 5′ and 3′ untranslated regions, suggesting that modes of regulation may have diverged across species. Thirty-one conserved putative regulatory element binding motifs were identified in the CARD15 intronic sequence of seven species. To assess the extent of genetic diversity within bovine CARD15, 41 individuals from two subspecies were sequenced and screened for polymorphisms. Thirty-six single nucleotide polymorphisms (SNPs) were identified. Finally, 20 subspecies-specific haplotypes were predicted with 7 and 13 unique haplotypes explaining the diversity within B. taurus taurus and B. taurus indicus animals, respectively. Strong evidence for a simple causal relationship between these SNP loci and their haplotypes with Johne's disease was not detected.