To investigate the rate of hypoxaemic acute respiratory failure (hARF) on patients undergoing surgery for non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy, to describe clinical and radiological findings and to explore potential risk factors for this complication. Retrospective review of medical records of all patients who underwent surgery for NSCLC after neoadjuvant chemotherapy at a single centre between 2014 and 2021. Computed tomography scans of patients who developed hARF were reviewed by an experienced radiologist to provide a quantitative assessment of radiologic alterations. The final cohort consisted of 211 patients. Major morbidity was 13.3% (28/211) and hARF was the most common major complication (n = 11, 5.2%). Postoperative mortality was 1.9% (4/211) and occurred only in patients who experienced hARF. Most patients who experienced hARF underwent major procedures, including pneumonectomy (n = 3), lobectomy with chest wall resection (n = 3), bronchial or vascular reconstructions (n = 3) and extended or bilateral resections (n = 2). Analysis of computed tomography findings revealed that crazy paving and ground glass were the most common alterations and were more represented in the non-operated lung. Male gender, current smoking status, pathologic stage III-IV and operative time resulted significant risk factors for hARF at univariable analysis (P < 0.05). hARF is the main cause of major morbidity and mortality after neoadjuvant therapy and surgery for NSCLC and occurs more frequently after complex and lengthier surgical procedures. Overall, our findings suggest that operative time may represent the most important risk factor for hARF.