Summary Background Selection of heath-related quality of life (HRQL) instruments that are most responsive to changes in HRQL prevents investigators from drawing false-negative conclusions about the effectiveness of an intervention. The objective of this study was to compare the responsiveness of the Chronic Respiratory Questionnaire (CRQ), the St. Georges Respiratory Questionnaire (SGRQ) and four other HRQL instruments. Methods We enrolled 177 patients with chronic lung disease, primarily COPD (93%), who completed 8 weeks of respiratory rehabilitation. Patients completed the CRQ, the SGRQ and four generic measures (SF-36, Feeling Thermometer, Standard Gamble and Health Utilities index 3) at the beginning of the rehabilitation program and 12 weeks thereafter. We calculated standardized response means (SRMs) for each instrument, from the change score divided by the standard deviation of the change score. Results We observed the largest SRM for the CRQ (0.24–0.66 for the four CRQ domains on the interviewer-administered and 0.56–0.84 for the self-administered format) and the SGRQ (0.33–0.51 for the three SGRQ domains and total score). The CRQ dyspnea domain was statistically significantly more responsive than any other instrument including the SGRQ. For the SGRQ, the total and impacts domain were significantly more responsive than the generic and preference-based instruments. Conclusions This study confirms that the CRQ and SGRQ are substantially more responsive than generic measures, and suggests particularly strong responsiveness for the self-administered CRQ.