The mouse mutant carries a mutation in the F-box only 11 gene () and heterozygous animals display conductive deafness due to the development of otitis media (OM). The locus is also associated with chronic otitis media with effusion (COME) and recurrent OM in humans. The mutation affects the ability of FBXO11 to stabilize p53 that leads to perturbation in the TGF-beta/Smad2 signaling pathway important in immunity and inflammation. In the current study, we evaluated the effect of the mutation on the immune cell content using multicolor flow cytometry. In blood of heterozygotes, we observed a significant increase in the number of NK, dendritic (CD11b+), neutrophils, and natural killer T (NKT) cells and a significant decrease in effector T-helper and B-lymphocytes compared to wild-type controls. The percentage of NK cells significantly decreased in the lungs of heterozygotes, with a concomitant reduction in B-lymphocytes and T-cytotoxic cells. In the spleen, heterozygotes displayed a significant decrease in mature B-lymphocytes, effector T-helper, and naïve T-cytotoxic cells. Neutrophils, dendritic, and NKT cells dominated bulla fluid in heterozygote mice. Similar analysis carried out on heterozygotes, which carry a null allele, showed no difference when compared to wild-type. Cytokine/chemokine analysis revealed a significant increase in the G-CSF, GM-CSF, sTNFRI, TPO, and IL-7 levels in heterozygote serum compared to wild-type. This analysis increases our understanding of the role played by , a gene associated with human OM, in the systemic and localized cellular immune response associated with increased susceptibility to OM.