To examine whether the expression levels of endogenous H2S synthases and hedgehog (Hh) signaling pathway components correlate with the clinicopathological characteristics of papillary thyroid cancer (PTC) patients. A retrospective analysis was conducted of clinicopathological data obtained from 176 patients diagnosed with PTC, and immunohistochemical methods were used to detect the expression levels of endogenous H2S synthases cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MPST), as well as three molecules in the Hh signaling pathway: sonic hedgehog (SHH), patched (PTCH), and smoothened (SMO). Specimens of PTC tissue (n=176) and normal para-cancerous thyroid tissue (n=134) were obtained from 176 patients who underwent a total thyroidectomy or thyroid glandular follicle and isthmus resection and analyzed by immunohistochemical methods for their levels of CSE, CBS, MPST, SHH, PTCH, and SMO expression. We found that CSE was overexpressed in PTC tissues, while CBS and MPST were only slightly expressed in PTC tissues at levels similar to those in adjacent normal tissues. The levels of CSE expression were positively correlated with tumor size, extrathyroidal extension (ETE), and lymph node metastasis (LNM), but were not correlated with patient gender, age, or TNM stage. SHH, PTCH, and SMO Hh signaling pathway components were widely expressed in PTC tissues, and their expression correlated with larger tumor size, ETE, and LNM, but not with patient gender, age, or TNM stage, suggesting that activation of the Hh signaling pathway is involved in thyroid tumor progression. These data suggest that a high level of CSE expression accompanied by Hh signaling pathway activation is involved in the pathogenesis and progression of PTC. IJCEP Copyright © 2018.