In this study, we evaluated: (1) ACE2 and TMPRSS2 expression in the airways of smokers with COPD, compared to smoker and never smoker (NS) controls, and (2) ACE2 expression in lungs of mice acutely and chronically exposed to CS; and (3) the effects of CS extract (CSE) or direct CS exposure on SARS-CoV-2 in vitro infection in Calu3 lung adenocarcinoma epithelial cells and differentiated primary human bronchial epithelium. Here, ACE2 is linked to chronic obstructive pulmonary disease.