Caseous lymphadenitis (CLA), a chronic, highly contagious disease in sheep and goats with zoonotic implications, significantly affects animal health and productivity. It is caused by Corynebacterium pseudotuberculosis (Cps), a facultative anaerobic, gram-positive bacterium, leading to abscesses in lymphatic tissues and internal organs. Rare zoonotic transmission poses risks to individuals handling infected animals. CLA is poorly responsive to antibiotics, making its management costly and challenging, which highlights the need for improved strategies. This study explored host genomic factors affecting antibody responses to Cps to identify genetic markers linked to disease susceptibility or resistance. Blood samples from 321 Suffolk sheep aged 2-8 years from four Czech herds were analyzed over four years. Animals were classified as healthy or diseased using two commercial ELISAs detecting Cps antigens. Genotyping of genomic DNA employed the GeneSeek(R) Genomic ProfilerTM Ovine 50K array, analyzing 41,301 SNP markers. A genome-wide association study (case-control GWAS) using GCTA software included 143 seropositive (diseased) and 178 seronegative (healthy) sheep to determine genetic associations with antibody responses to a phospholipase D antigen of Cps. GWAS identified two suggestive SNPs (p-value < 3.42 x 10-5) on chromosomes 11 and 20, with the most significant SNP in the TRIM16 (tripartite motif containing 16 gene). Gene Ontology analysis within +-500 kb of these SNPs identified immune-related processes, such as antigen processing via MHC class I and II, Th17 mucosal cell differentiation, cellular autophagy, and phagosome activity, as mechanisms influencing CLA susceptibility. These findings highlight genomic regions and immune pathways associated with resistance to CLA. This study provides insights into the genetic basis of antibody responses to C. pseudotuberculosis, offering potential markers for breeding strategies to improve disease resistance in sheep.