Abstract Objective—To investigate the possibility that variants in the acidic or basic keratin genes or in desmoglein 1 may cause the clinical manifestation of familial footpad hyperkeratosis in Irish Terriers. Animals—11 dogs belonging to 2 related affected pedigrees of Irish Terriers. Procedure—Genomic DNA was extracted from blood samples obtained from each dog. The DNA markers linked to the genes keratin 2, keratin 9, and desmoglein 1 were amplified by use of a polymerase chain reaction technique, and length of the products was determined by use of an automatic DNA analyzer. Results—All tested markers yielded information. None of the markers (genotype) cosegregated with the clinical status of the dogs (phenotype) in the 2 pedigrees. Conclusions and Clinical Relevance—Mutations in the genes encoding keratin 2 and 9 as well as desmoglein 1 are highly unlikely to be the primary cause of familial footpad hyperkeratosis in Irish Terriers. (Am J Vet Res 2003;64:715–720)