Background: The Ibizan Hound is a canine breed native to the Mediterranean region, where leishmaniosis is an endemic zoonosis. Several studies indicate low prevalence of this disease in these dogs but the underlying molecular mechanism remains unknown. Methods: In this study, qualitative immunological and genomic profiles of this breed have been analyzed. Results: Our analysis shows relevant differences between the cytokine serum profile of Ibizan Hound dogs and previously published data from other canine strains. Additionally, several genetic risk variants related to the immune response, regulation of the immune system, and genes encoding cytokines and their receptors have been studied. The most relevant genes that presented such fixed polymorphisms were IFNG and IL6R. Other variants with frequencies ≥ 0.7 were found in the genes ARHGAP18, DAPK1, GNAI2, MITF, IL12RB1, LTBP1, SCL28A3, SCL35D2, PTPN22, CIITA, THEMIS, and CD180. Epigenetic regulatory genes such as HEY2 and L3MBTL3 showed also intronic polymorphisms. Conclusions: Our analysis and results indicate that the regulation of immune responses is different in Ibizan Hounds compared to other breeds. Future studies are needed to elucidate whether these differences are related to the low prevalence of L. infantum infection in the Ibizan Hound.