Background <p>This study sought to elucidate CT-derived quantitative imaging biomarkers and clinical parameters predisposing to arterial oxygen desaturation during one-lung ventilation (OLV) in individuals undergoing repeated lung resections, to improve understanding of preoperative factors associated with hypoxemia risk during OLV in this population.</p> Methods <p>A retrospective analysis was performed on 139 patients who underwent repeated lung resections between January 2022 and December 2023 at Yunnan Cancer Hospital. Preoperative CT-derived quantitative imaging biomarkers, including functional lung volume percentage (FLV%) and low attenuation volume percentage (LAV%), were extracted from routine CT scans alongside other clinical variables. Thirteen potential risk factors were first examined using Pearson’s correlation and univariate regression analysis to identify variables significantly associated with hypoxemia. Variance inflation factor (VIF) tests were applied to exclude multicollinearity before performing multivariable logistic regression to determine independent risk factors.</p> Results <p>The incidence of hypoxemia during OLV in repeated lung resections was 16.55%. Four independent risk factors were identified: proportion of functional lung volume in the dependent lung as a key quantitative imaging biomarker (FLV%-dependent lung: OR 0.92, 95% CI 0.85–0.99; <i>p</i> = 0.038), a history of prior hypoxemia (OR 7.64, 95% CI 1.65–35.31; <i>p</i> = 0.009), moderate to severe postoperative pain at 48 hours (OR 5.59, 95% CI 1.95–16.03; <i>p</i> = 0.001), and forced expiratory volume in one second (FEV1% predicted: OR 1.04, 95% CI 1.00–1.08; <i>p</i> = 0.038).</p> Conclusion <p>CT-derived quantitative imaging biomarker FLV%-dependent lung and FEV₁% predicted, a history of prior hypoxemia and moderate-to-severe acute postoperative pain within 48 hours after the initial lung resection, are associated with hypoxemia risk in repeated lung resections.</p>