Background: Papillary thyroid carcinoma (PTC) is the most prevalent malignancy of the endocrine system. This study was aimed at evaluating the serum substance P (SP) levels, the tissue distribution of Neurokinin-1 receptors (NK1-R), and their possible diagnostic value in PTC. Method: The present case-control study included 31 healthy volunteers and 31 cases (age range: 25-64, 40.26 +/- 12.77), who were primarily diagnosed with PTC and were candidates for total thyroidectomy. Pre-operative serum level of SP was measured using a commercial ELISA kit. The tissue distribution of NK1-R was assessed immunohistochemically. Results: The serum level of SP in the patient group was higher than the healthy volunteers (P = 0.005). Besides, the expression of NK1-R was higher in tumoral tissues compared with their normal surroundings (P = 0.005). However, we observed no significant correlation between either SP level or NK1-R expression and the disease stage or lymph node involvement. Conclusion: SP level and NK1-R expression were upregulated in PTC patients, showing the involvement of SP/NK1R complex in PTC pathophysiology. Nonetheless, proposing SP/NK1R as a diagnostic factor requires further studies because we found no correlation between SP/NK1R and clinical stage or lymph node involvement.