Background: Hepsin is known as a cell-surface serine protease expressed predominantly in the liver. Hepsin-deficient mice show resistance to high-fat diet-induced obesity, hyperlipidemia, and hyperglycemia. Up to the present, the physiological function of hepsin has not been fully determined. Hepsin may play significant and specific roles in diabetes. Objectives: This study aimed to evaluate the relationship between hepsin protein concentrations in serum and type 2 diabetes mellitus (T2DM) and elucidate possible associations with disease activity andinflammatory and metabolic parameters. To the best of our knowledge, this is the first study evaluating the relationship between hepsin, lymphocyte-to-C-reactive protein ratio (LCR), and type 2 diabetes in humans in the existingliterature. Methods: This case-control study included 60 patients (30 males and 30 females) diagnosed with type 2 diabetes, according to American Diabetes Association's criteria, and 30 healthy controls (14 males and 16 females) with similar demographic characteristics. Several laboratory parameters were assessed including fasting glucose, total cholesterol, insulin, hemoglobin A1c, gamma-glutamyl transferase, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, C-reactive protein, atherogenic index of plasma, LCR, monocyte-to-neutrophil ratio, neutrophil-to-lymphocyte ratio, and serum hepsin levels. Results: The type 2 diabetes group had significantly higher LCR than controls (P<0. 016). Correlation analysis in the patient group showed a statistically significant relationship between hepsin and LCR (rho=0. 296, P=0. 02). Hepsin was negatively correlated with CRP in the patient group (rho=-0. 333, P=0. 01). Correlation analysis in the patient group showed a statistically significant relationship between hepsin and cholesterol (rho= 0. 29, P= 0. 02). Age was positively correlated with hepsin in the patient group (rho= 0. 267, P=0. 04). There was no statistically significant difference in serum hepsin levels between the diabetes group and the control group (P=0. 157). Conclusion: To the best of our knowledge, this is the first study assessing the hepsin levels in patients with T2DM. Our results indicated that increased levels of hepsin could be associated with the inflammatory processes. Similar results were not found for diabetes. However, it is recommended that similar studies should be conducted in larger patient populations.