BACKGROUND Depression is a major comorbidity in Chronic Obstructive Pulmonary Disease (COPD). The aim of this study was to explore cytokine levels, and socio-demographic and clinical factors that may affect COPD-related depression. MATERIAL AND METHODS This prospective study enrolled 53 consecutive COPD patients, without any other lower respiratory tract diseases, psychiatric disorders, family history or cognitive disorders, who were hospitalized in the Department of Respiratory Medicine of Hefei First People's Hospital, China between October 2015 and October 2016. All patients were investigated for depression, and the serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8) and Tumor Necrosis Factor-α (TNF-α) were measured. The factors that may affect COPD-related depression were analyzed. RESULTS There were 40 (75.47%) patients with depression. There were differences in gender, smoking, time of cough, education, forced expiratory volume in the first second (FEV1) and serum CRP levels between COPD patients with or without depression. In a univariate analysis, gender, smoking, education, FEV1, time of cough and serum CRP level were associated with depression. In a multivariate logistic regression model, serum CRP level and FEV1 were risk factors for depression. CONCLUSIONS Male patients, heavy smoking, higher academic qualifications, cough, and high serum CRP level were linked to higher incidence rate of depression. High serum CRP level and low FEV1 were the risk factors for COPD-related depression.