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Chronic obstructive pulmonary disease (COPD) and cystic fibrosis share key clinical features such as chronic airway inflammation and obstructive airflow limitation, and both diseases may lead to chronic respiratory failure and death. Cigarette smoke, well-known to be the major cause of COPD, contributes to suppression of the expression and function of cystic fibrosis transmembrane conductance regulator protein. Likewise, there is evidence that cystic fibrosis transmembrane conductance regulator dysfunction may contribute to key molecular pathways involved in the pathogenesis of COPD. We present 3 adult patients with extensive cigarette smoking histories and COPD who were subsequently diagnosed with cystic fibrosis and describe the management strategy implemented.