Footrot is an acute and highly infectious disease of cattle that develops between the claws of the hoof and is caused by the Gram-negative anaerobic bacterium Fusobacterium necrophorum, which is present in the rumen and feces of normal cattle and their environment.Plasma is an amorphous and important component of blood and changes in the quantity and quality of plasma proteins are associated with physiological or pathological states in humans and other animals.However, the plasma protein profiles of cattle with footrot are not fully understood, and there are still a great many unknown potential disease-associated proteins.In this study, the plasma proteome of healthy dairy cattle and those with footrot was investigated using a shotgun LC-MS/MS approach.In total, 648 proteins were identified in healthy plasma samples, of which 234 were non-redundant proteins and 123 were high-confidence proteins;712 proteins were identified from footrot plasma samples, of which 272 were non-redundant proteins and 138 were high-confidence proteins.The high-confidence proteins showed significant differences between healthy and footrot plasma samples in molecular weight, isoelectric points and the Gene Ontology categories.22 proteins were found that may differentiate between the two sets of plasma proteins, of which 16 potential differential expression (PDE) proteins from footrot plasma involved in immunoglobulins, innate immune recognition molecules, acute phase proteins, regulatory proteins, and cell adhesion and cytoskeletal proteins 6 PDE proteins from healthy plasma involved in regulatory proteins, cytoskeletal proteins and coagulation factors.Of these PDE proteins, haptoglobin,SERPINA10 protein, afamin precursor, haptoglobin precursor, apolipoprotein D, predicted peptidoglycan recognition protein L (PGRP-L) and keratan sugate proteoglycan (KS-PG) were suggested to be potential footrot-associated factors.The PDE proteins haptoglobin, PGRP-L and KS-PG were highlighted as potential biomarkers of footrot in cattle.The haptoglobin has been shown to be a useful biomarker for monitoring the occurrence and severity of inflammatory responses in cattle with mastitis, pneumonia, enteritis, peritonitis, endocarditis, abscesses, endometritis and hoof disease.Here, haptoglobin was verified as plasma inflammatory biomarkers of footrot in dairy cattle.The predicted PGRP-L may be necessary for recognition of the innate immune activators of the Gram-negative anaerobic bacterium F.necrophorum.The keratan sulfate in blood has been shown to be a marker of cartilage catabolism.The KS-PG, which was found in the plasma from footrot-affected dairy cattle, may reflect catabolism of hoof cartilage, and it has been suggested to be a potential marker for evaluation of foot damage in dairy cattle.The resulting protein lists and potential differentially expressed proteins may provide valuable information to increase understanding of plasma protein profiles in cattle and to assist studies of footrot-associated factors.