Background Numerous instruments are available to measure health-related quality of life (HRQoL) in patients with Chronic Obstructive Pulmonary Disease (COPD), covering a wide array of domains ranging from symptoms such as dyspnea, cough and wheezing, to social and emotional functioning. Currently no information or guide is available yet to aid the selection of domains for a particular study or disease population. The aim of this paper is to identify which domains of HRQoL are most important with respect to COPD, from the patient perspective. Methods Twenty-one Dutch patients with COPD were asked to describe important domains impacted by COPD freely; second, they were presented with cues (domains from the Patient-Reported Outcomes Measurement Information System (PROMIS) framework) and were asked to select the domains that were most relevant to them. During the interview, the patients were asked to indicate in which way the selected domains impact their lives. Both the answers to the open question, and the patient statements motivating nomination of PROMIS domains were coded into themes. Results The most relevant (sub)domains of HRQoL for patients with COPD were: physical health (fatigue, physical functioning), social health (instrumental support, ability to participate in social roles and activities, companionship, and emotional support), and coping with COPD. Conclusion We identified which domains of HRQoL are most important to patients with COPD. One of these (coping with COPD) is not explicitly covered by PROMIS, or by traditional questionnaires that are used to measure HRQoL in COPD.