Objective Patients with end-stage lung disease (ESLD) experience significant decrements in quality of life (QOL). Although coping strategies are related to QOL in patients with ESLD, the extent to which specific native lung disease moderates this relationship is unknown. Methods We investigated the relationship between coping, native lung disease, and QOL among 187 patients awaiting lung transplantation, including 139 patients with chronic obstructive pulmonary disease (COPD) and 48 with cystic fibrosis (CF). Participants completed a psychosocial battery assessing psychological QOL, physical QOL, and coping strategies. Results For both COPD and CF patients, higher levels of Active Coping (P<.0001) and lower levels of Disengagement (P<.0001) were associated with better psychological QOL. For physical QOL, we observed a Native Disease×Coping interaction (P=.01) such that Active Coping was associated with better physical QOL in patients with COPD but not in patients with CF. Conclusions The relationship between coping and QOL may vary as a function of native lung disease. Patients' native disease may need to be considered in order to develop effective interventions to help patients cope successfully with ESLD.