BACKGROUND: C1q TNF related protein 3 (CTRP3) is an adipokine secreted from adipose tissue. Previous studies have suggested that CTRP3 improves insulin sensitivity and reduces inflammation. Human studies have evaluated circulating levels of this adipokine in patients with diabetes mellitus (DM), diabetic retinopathy, metabolic syndrome, and coronary artery diseases. However, circulating levels of this adipokine in patients with diabetic nephropathy have not been evaluated. The present study aimed to assess serum levels of CTRP3 in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (T2DM-NP) and its relationship with metabolic and inflammatory markers. METHODS: This cross-sectional study was performed on 55 controls, 54 patients with T2DM, and 55 patients with T2DM-NP. Serum levels of CTRP3, adiponectin, TNF-α, and IL-6 were measured by ELISA technique. RESULTS: Serum levels of CTRP3 were significantly lower in patients with T2DM (257.61 ± 69.79 ng/mL, p < 0.001) and T2DM-NP (222.03 ± 51.99 ng/mL, p < 0.001) compared to controls (328.17 ± 80.73 ng/mL), and those with T2DM-NP compared to T2DM group. CTRP3 was independently associated with HOMA-IR (r = -0.327, p < 0.05) and adiponectin (r = 0.436, p < 0.01) in T2DM group. In T2DM-NP patients, CTRP3 independently was associated with eGFR (r = 0.428, p < 0.01) and HOMA-IR (r = -0.436, p < 0.01). Furthermore, CTRP3 revealed a ability to differentiate T2DM-NP patients from controls (area under curve (95% confidence interval): 0.881 (0.820-0.943) and p < 0.001). CONCLUSION: Decreased serum levels of CTRP3 in patients with T2DM and diabetic nephropathy and its association with pathologic mechanism in these patients suggested a possible role for CTRP3 in pathogenesis of diabetic nephropathy; nevertheless, further studies are required in this regard.