Caseous lymphadenitis (CLA) is a chronic and highly contagious disease that is widespread among sheep and goats and adversely affects animal welfare and production. This study aimed to reveal the host genomic influences on Corynebacterium pseudotuberculosis antibody levels as indicators of disease susceptibility or resistance, thereby potentially identifying genetic markers associated with these traits. Blood samples were collected from 321 sheep from four large Czech sheep herds. Animals of the Suffolk breed, ranging in age from 2 to 8 years, were sampled regularly once a year for 4 years. The sheep were classified into healthy and diseased groups based on two different commercial enzyme-linked immunosorbent assay (ELISA) serological antigen tests. Genomic DNA was genotyped with the GeneSeek (R) Genomic Profiler (TM) Ovine 50 K, and 41 301 markers were used for the genome-wide association analysis (GWAS). A case-control GWAS including 143 seropositive and 178 seronegative sheep was conducted to assess the relationship between the sheep genome and the antibody response to a phospholipase D antigen of C. pseudotuberculosis using GCTA software. The study revealed two suggestive SNPs (single-nucleotide polymorphisms) on chromosomes 11 and 20, with the most significant SNP in the first exon of the TRIM16 (tripartite-motif-containing 16) gene. By analysing genomic alterations and their context between positive and negative animals, including a gene ontology (GO) analysis of genes within +/- 500 kb regions of the suggestive SNPs, we identified genes and immune-related processes and pathways potentially influencing CLA susceptibility. These include antigen processing and presentation of exogenous peptides via major histocompatibility complex (MHC) class I and II, Th17 mucosal cell differentiation, cellular autophagy, and phagosome-related mechanisms.