We aimed to investigate the changes in the levels of high-molecular-weight (HMW) adiponectin, adiponectin receptors, and cytokines in patients with chronic obstructive pulmonary disease (COPD), as well as their potential relationships. Forty-one patients who underwent lobectomy for lung lesions and had a clear postoperative pathological diagnosis were divided into the non-COPD (N = 23) and COPD (N = 18) groups. HMW adiponectin, cytokine, and T-cadherin levels in serum and tissues were detected by enzyme-linked immunosorbent assay. The levels of HMW adiponectin and cytokine (interleukin [IL]-6, IL-10, surfactant protein D, 4-hydroxynonenal, tumor necrosis factor-alpha, and C reactive protein) in the serum and tissues increased in the COPD group compared to those in the non-COPD group. Patients with COPD exhibited AdipoR1 upregulation and AdipoR2 downregulation. Although T-cadherin did not differ significantly between patients with and those without COPD, its expression was elevated during the progression from COPD with benign lung lesions to combined lung cancer. Furthermore, the HMW adiponectin levels were significantly correlated with the cytokine levels and the clinical characteristics of COPD. HMW adiponectin and its receptors affect the inflammatory process in COPD and may further contribute to the progression of the disease to malignancy.