Abstract: Hepatitis C is a disease with significant global impact, it is the most common cause of chronic liver diseases, and in addition it causes insulin resistance (IR) leading to increase the risk of type 2 diabetes mellitus (DM). This current study aimed to assess the relationship between serum tumor necrosis factor-α (TNF-α) , insulin resistance (IR) and type 2 DM in patients HCV. Patients and Methods: The study cohort consists of 91 subjects stratified into 4 groups; Group (I): Include 25 HCV patients without DM, Group (II): Include 25 HCV diabetic patients, Group (III): Include 25 diabetic patients without HCV infection and group (IV): Include 16 healthy subjects serving as a control group. All patients were subjected to full history taking, thorough clinical examination and estimation of body mass index (BMI). Anti-HCVAb was detected by the 3rd generation (ELISA) test and was confirmed by PCR . Assessment of fasting plasma insulin level (FBI) and TNF-α were done by ELISA test, while assessment of the insulin resistance was estimated by Homeostatic Model Assessment (HOMA-IR). Results: higher mean levels of (FBS), 2 hr (2 HPP) and fasting plasma insulin (FSI) were detected in group II (HCV+DM) compared to other groups with statistically significant differences between all the studied groups (P value < 0.001), consequently HCV diabetic patients were found to have significant higher IR than HCV patients without DM, diabetic patients alone and control group (P value < 0.001). Furthermore, there was highly statistically significant differences between all studied groups as regard level of TNF-α (P value < 0.001) with higher mean level in group I (HCV group). Insignificant difference in level of TNF-α in HCV patients with or without IR (P value = 0.072). Insignificant positive correlation between HOMA-IR and TNF-α (P value = 0.63(. Conclusion: chronic HCV patients have significantly elevated fasting plasma insulin level, TNF-α and significant IR and there was insignificant correlation between HOMA-IR and TNF-α.