Background Ticks are obligate hematophagous arthropods that synthesize the glycan Gal alpha 1-3Gal beta 1-(3)4GlcNAc-R (alpha-Gal) associated with the alpha-gal syndrome (AGS) or allergy to mammalian meat consumption. Research design and methods In this study, we used a proteomics approach to characterize tick proteins in salivary glands (sialome SG), secreted saliva (sialome SA) and with alpha-Gal modification (alphagalactome SG and SA) in model tick species associated with the AGS in the United States (Amblyomma americanum) and Australia (Ixodes holocyclus). Selected proteins reactive to sera (IgE) from patients with AGS were identified to advance in the identification of possible proteins associated with the AGS. For comparative analysis, the alpha-Gal content was measured in various tick species. Results The results confirmed that ticks produce proteins with alpha-Gal modifications and secreted into saliva during feeding. Proteins identified in tick alphagalactome SA by sera from patients with severe AGS symptomatology may constitute candidate disease biomarkers. Conclusions The results support the presence of tick-derived proteins with alpha-Gal modifications in the saliva with potential implications in AGS and other disorders and protective capacity against tick infestations and pathogen infection. Future research should focus on the characterization of the function of tick glycoproteins with alpha-Gal in tick biology and AGS.