Background: Diabetes and obesity are associated with an increased risk of cardiovascular disease. Irisin is a newly recognized peptidic myokine with anti-obesity and anti-diabetic properties. This study aims to investigate the relationship between serum irisin levels with cardiometabolic biomarkers in patients with type 2 diabetes mellitus (T2DM). Methods: In this comparative cross- sectional study, 80 T2DM patients and 80 control participants (adjusted by age, body mass index (BMI), and physical activity) referring to Bou Ali Hospital in Zahedan, Iran, were enrolled. Serum irisin concentrations, anthropometric, and biochemical parameters were assessed. Results: Serum irisin level was significantly lower in T2DM patients compared to control group. Multiple linear regression analysis revealed that after adjustment for age, irisin was negatively associated with waist circumference (WC, P < 0.01) and waist to height ratio (WHtR, P < 0.01), homeostasis model assessment insulin resistance (HOMA-IR, P = 0.009), triglycerides (TG, P = 0.016), and positively associated with high density lipoprotein cholesterol (HDL-c, P = 0.03) in diabetic patients. Conclusion: The findings suggest that irisin can be used as a marker for predicting of obesity-related cardiometabolic biomarkers, insulin resistance, and incident T2DM.