Ticks and tick-borne diseases have a detrimental impact on livestock production with estimated losses of around $200 million per year in Australia alone. Host resistance to ticks is heritable, with a within-breed heritability of around 0.35, and large differences between breeds. Previously a QTL for tick burden was detected on BTA14 at ~ 72Mb distal to the centromere, near the gene RIPK2. To confirm these associations, genotypes of newly identified SNP in the RIPK2 and also SNP derived from the bovine genome sequence were collected from two samples, one of 1,122 taurine dairy cattle and one of 761 zebu and zebu-composite beef cattle. We confirmed that SNP and haplotypes from this region, including from the RIPK2, were associated with tick burden in both dairy and beef cattle. To determine whether RIPK2 influences response to tick salivary gland extract (SGE), an immunization experiment with tick SGE in RIPK2 knockout (C57BL/6 RIPK2 -/-) mouse strain was conducted. There was a significant (P < 0.05) reduction in IgG production in the RIPK2 -/- mouse to the SGE compared to both, its background strain C57BL/6 as well as the outbred CD1 mouse strain used for comparison. In addition, antibody generated by RIPK2 -/- mice recognized a different set of antigens within SGE when compared to parental-derived antibody. In summary, the SNP association with tick burden at BTA14 was confirmed and quantitative and qualitative differences in antibody production were observed between RIPK2 -/- and wild-type mice.