Background: Despite clinical and different basic investigations, the role of plasma adipokines, such as adiponectin as a precise predictor of the risk of colorectal cancer (CRC) is still conflicting. Objectives: This study investigated the association between CRC and insulin resistance, obesity, and plasma adiponectin level for the first time in Iran. Methods: A total of 80 subjects (including 45 CRC patients and 35 healthy individuals) were enrolled in this case-control study. Demographic, anthropometric, and clinical data were recorded, and serum levels of adiponectin, insulin, and glucose were evaluated using enzyme-linked immunosorbent assay and glucose oxidase technique, respectively. Insulin resistance index (HOMA-IR) was measured as well. Results: The mean±, SD plasma adiponectin concentration in the CRC patients (7. 98±, 0. 64 ng/ml) was not significantly higher, than the control group (8. 05±, 1. 14 ng/mL). However, the mean±, SD of HOMA-IR and plasma glucose levels (1. 81±, 0. 61 and 7. 64±, 1. 34 mm/L, respectively) of the CRC group were significantly higher (P<0. 05), compared to the control group (1. 37±, 0. 3 and 119±, 1. 1 mg/dL, respectively),though, plasma insulin wasn’, t significantly different in the two study groups. Following the stratification of CRC patients according to the tumor site, a significantly lower level of adiponectin (7. 36 ±, 1. 1 ng/ml) (P<0. 05) and a significantly higher level of HOMAIR (2. 08±, 0. 44) were observed in patients with colon cancer (P<0. 005), compared to the controls. Regression among the plasma adiponectin and the plasma insulin and HOMA-IR was negative in the control and CRC groups. Conclusion: Insulin resistance has an important role in the development of CRC, especially in the genesis colon cancer, regardless of the change it causes in plasma levels of adiponectin.