Objective: Current ventilation and perfusion dose– response studies focus on single-modalities (ventilation or perfusion) and perform pulmonary-toxicity assessment related to radiotherapy on a population-based basis. This study aims at quantitative and clinical evaluation of intrapatient differences between ventilation and perfusion dose–responses among lung cancer patients treated with radiotherapy. Methods: 20 patients enrolled on a prospective functional avoidance protocol underwent single photon emission computed tomography-CT ventilation and perfusion scans pre-and post-radiotherapy. Relative changes in pre-to post-treatment ventilation and perfusion in lung regions receiving ≥20 Gy were calculated. In addition, the slopes of the linear fit to the relative ventilation and perfusion changes in regions receiving 0–60 Gy were calculated. A radiologist read and assigned a functional defect score to pre-and post-treatment ventilation/perfusion scans. Results: 25% of patients had a difference >35% between ventilation and perfusion pre-to post-treatment changes and 20–30% of patients had opposite directions for ventilation and perfusion pre-to post-treatment changes. Using a semi-quantitative scale, radiologist assessment showed that 20% of patients had different pre-to post-treatment ventilation changes when compared to pre-to post-treatment perfusion changes. Conclusion: Our data showed that ventilation dose– response can differ from perfusion dose–response for 20–30% of patients. Therefore, when performing thoracic dose–response in cancer patients, it is insuffi-cient to look at ventilation or perfusion alone; but rather both modes of functional imaging may be needed when predicting for clinical outcomes. Advances in knowledge: The significance of this study can be highlighted by the differences between the intra-patient dose–response assessments of this analysis compared to existing population-based dose–response analyses. Elucidating intrapatient ventilation and perfusion dose–response differences may be valuable in predicting pulmonary toxicity in lung cancer patients post-radiotherapy.