Abstract Chronic obstructive pulmonary disease (COPD) is often associated with the co-occurrence of extra-pulmonary diseases, yet the underlying pathophysiology of comorbidities is poorly understood. In COPD patients, the bronchial epithelium often displays cellular damage and is chronically inflamed. The current study aimed to identify differentially expressed genes in bronchial epithelium of COPD patients with and without comorbidities. To this end, a genome-wide differential gene expression analysis was performed on bronchial epithelial samples of 123 severe COPD patients with and without the following comorbidities: anxiety, atherosclerosis, depression, hypercholesterolemia, hypertension, muscle wasting, osteoporosis, and low BMI. COPD patients with osteoporosis displayed higher expression of COL6A3 and lower expression of PHEX. Furthermore, COPD patients with hypercholesterolemia displayed a distinct bronchial epithelial gene expression profile, with 162 differentially expressed genes. No differentially expressed genes were identified for the other comorbidities. This study identified differentially expressed bronchial epithelial genes associated with osteoporosis and hypercholesterolemia in COPD patients.