Objective Cardiac autonomic neuropathy (CAN) is a common complication of diabetes associated with poor prognosis. It is thought that adipocytokines contribute to the increased risk of vascular complications in patients with type 2 diabetes mellitus (T2DM). However, literature data on the association between CAN with adipocytokines such as leptin, TNF-α, adiponectin in subjects with T2DM are limited. Therefore, in the present study, we examined the relationship between fasting serum adiponectin, leptin, and TNF-α and CAN in Korean T2DM patients. Methods A total of 148 T2DM patients were recruited. CAN was assessed by the five tests according to the Ewing's protocol and the time and frequency domain of heart rate variability (HRV) was evaluated. Serum TNF-α and adiponectin levels were measured using enzyme-linked immunosorbent assay and serum leptin levels were measured using radioimmunoassay. Results Although, the mean levels of leptin, TNF-α and adiponectin were not significantly different between the groups with and without CAN, the levels of leptin and adiponectin had a tendency to increase as the score of CAN increased (p=0.049, p=0.005). LF in upright position were higher in without patients with CAN than with CAN borderline significantly (p=0.05). Serum leptin levels showed positive correlation with HF and negative correlation with LF/HF ratio in upright position. Regarding TNF-α, significant negative correlation was observed with SDNN, RMSSD and HF in upright position. Multivariate logistic regression analysis demonstrated that the odds of CAN increased with longer duration of diabetes (1.16, [1.03-1.31]) and higher HOMA-IR (1.68, [1.07-2.63]). The relative risks for presence of CAN in the highest tertile of the adiponectin levels were 39 (39.2, [3.92-391.9]) as compared to the patients in the lowest tertile of the adiponectin levels. Conclusion In the present study, higher serum adiponectin levels were associated with an increased risk for the presence of CAN. Also, score of CAN correlated with serum adiponectin and leptin. Serum adipocytokines such as leptin and TNF-α were significantly correlated with parameters of HRV, representative markers of CAN. Future prospective studies with larger numbers of patient are required to establish a direct relationship between plasma adipocytokine concentrations and the development or severity of CAN.