Previous studies have applied genomics and transcriptomics to identify the immune and genetic markers as key indicator traits for cattle tick susceptibility/resistance, however, results differed between breeds, and host proteomics and metabolomics were not considered. We used serum samples from Santa Gertrudis cattle phenotypically divided into groups as tick-resistant (TR) and -susceptible (TS) to conduct differential abundance analyses of protein profiles between the two groups. The serum proteins were digested into peptides followed by identification and quantification by sequential window acquisition of all instances of theoretical fragment ion mass spectrometry (SWATH-MS).