Scurs is a horn phenotype that exhibits as small corneous structures on the skull due to the deformed development of horn tissues.  Previous genome-wide association analysis of scurs in Soay sheep showed a significant association to the polled locus, relaxin-like receptor 2 (RXFP2).  However, the molecular mechanism underlying the development of scurs remains largely unknown.  In the present study, we performed an iTRAQ-based quantitative proteomic analysis of horn tissues from both scurs and normal two-horned and four-horned individuals among Altay sheep to identify the differentially expressed proteins (DEPs) responsible for the scurs phenotype.  In total, 232 proteins showed significant differential expression, and the most significant Gene ontology categories were the adhesion processes (biological adhesion (P=4.07×10^–17) and cell adhesion (P=3.7×10^–16)), multicellular organismal process (single-multicellular organism process (P=2.06×10^–11) and multicellular organismal process (P=2.29×10^–11)) and extracellular processes (extracellular matrix organization (P=4.77×10^–16) and extracellular structure organization (P=4.93×10–16)).  Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that extracellular matrix (ECM)-receptor interactions and focal adhesion pathways were the most significant pathways.  This finding is consistent with the reduced formation of extracellular matrix in scurs and the development of deformed horn tissues.  Our study helps to elucidate the inheritance pattern of sheep horn traits from the perspectives of downstream expressed proteins.