OBJECTIVES: Breathlessness is common in patients with advanced cancer and almost universal in advanced chronic obstructive pulmonary disease (COPD), but studies suggest their experiences of breathlessness vary. This report builds on these studies by providing quantitative evidence of differences in respiratory health-related quality of life (HRQoL) between these groups. Further, it explores the validity of the Chronic Respiratory Questionnaire (CRQ) in patients with cancer. METHODS: The CRQ-Original was completed within baseline interviews for a randomised controlled trial of a palliative intervention for intractable breathlessness due to advanced disease. Independent samples Mann-Whitney U tests were performed to identify significant differences in median scores for the four CRQ domains (mastery, dyspnoea, emotional function, fatigue) in patients with advanced COPD (n=73) or advanced cancer (n=67). The Minimally Clinically Important Difference of 0.5 was applied to determine clinical significance. RESULTS: Patients with advanced COPD scored lower across all four CRQ domains. This was statistically significant for dyspnoea, mastery and emotional function (p<0.05), and clinically significant for the latter two, suggesting poorer respiratory HRQoL. CONCLUSIONS: Patients with breathlessness due to advanced COPD have worse respiratory HRQoL than those with advanced cancer. This may result from greater burden of breathlessness in COPD due to condition longevity, lesser burden of breathlessness in cancer due to its episodic nature, or variance in palliative referral thresholds by disease group. Our results suggest that greater access to palliative care is needed in advanced COPD, and that formal psychometric testing of the CRQ may be warranted in cancer. TRIAL REGISTRATION NUMBER: NCT00678405.