ABSTRACT: Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer; however, the specific genes and signaling pathways involved in this cancer remain largely unclear. The present study analyzed three profile datasets, GSE6004, GSE29265 and GSE60542, which were comprised of 47 PTC and 41 normal thyroid tissue samples, to identify key genes and pathways associated with PTC. Initially, differentially-expressed genes (DEGs) between PTC and normal thyroid tissue were screened using R 3.4.0 (2017-04-21, R Foundation, Vienna, Austria, http://www.R-project.org/). These DEGs were then clustered by gene ontology functional terms and representative signaling pathways. Additionally, specific key gene nodes were filtered out from a constructed protein-protein interaction (PPI) network. The results identified a total of 423 shared DEGs associated with PTC, including 211 upregulated and 212 downregulated genes. These 423 genes were primarily enriched in glycosaminoglycan binding, sulfur compound binding, heparin binding, enzyme activator activity, peptidase activator activity and hsa04512: Extracellular matrix (ECM)-receptor interaction. A total of 21 central node genes were identified as key genes in the PTC disease process including complement factor D (CFD), Collagen Type I ? 1 Chain (COL1A1), Extracellular Matrix Protein 1 (ECM1) and Fibronectin 1 (FN1). These genes are involved in protease binding, G-protein coupled receptor binding, extracellular matrix structural constituent and peptidase regulator activity. To conclude, using bioinformatics analysis, the present study identified candidate DEGs and critical pathways in PTC that may improve the current understanding regarding the underlying mechanisms of PTC. These genes and pathways may be used as potential therapeutic targets of PTC in the future.