Background: Despite clinical and basic different investigations, the role of plasma adipokines, such as adiponectin as a precise predictor of the risk of colorectal cancer (CRC) is still conflicting. Aim: This study investigated the association between CRC and insulin resistance, obesity, and plasma adiponectin level for the first time in Iran. Method: 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 of the CRC patients (7.98±0.64 ng/ml) was not significantly higher, compared to that in the control group (8.05±1.14 ng/mL). 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); however, 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 HOMA-IR (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 was negative in the control and CRC groups. Conclusion: Insulin resistance has an important role in the development of CRC, especially in genesis colon cancer, regardless of the change that it causes in plasma levels of adiponectin