Purpose <p>Desflurane and sevoflurane are widely used for general anesthesia; however, it remains uncertain if sevoflurane might be preferable for patients with chronic respiratory inflammatory diseases. This study compared postoperative outcomes of desflurane and sevoflurane following gastrointestinal cancer surgery in patients with chronic obstructive pulmonary disease (COPD) or asthma.</p> Methods <p>We conducted a retrospective cohort study using the Japanese Diagnosis Procedure Combination database (April 2011–March 2022), identifying patients with COPD or asthma who underwent gastrointestinal cancer surgery. The primary outcome was postoperative pulmonary complications, including pneumonia, respiratory failure, mechanical ventilation &gt; 24&#xa0;h, and unplanned reintubation within 7&#xa0;days after surgery. Secondary outcomes were in-hospital mortality and postoperative stay. We conducted propensity score overlap weighting and instrumental variable analyses adjusted for confounders.</p> Results <p>We identified 24,243 COPD and 16,199 asthma patients. Propensity score overlap weighting showed no significant association between desflurane and increased postoperative pulmonary complications in COPD [adjusted risk difference (aRD) − 0.57%; 99% confidence interval (CI), − 1.8% to 0.60%] or asthma (aRD, − 0.62%; 99% CI, − 1.8% to 0.59%). In-hospital mortality did not differ significantly between groups in COPD (aRD, − 0.24%; 99% CI, − 0.76% to 0.29%) or asthma (aRD, 0.07%; 99% CI, − 0.45% to 0.59%). The postoperative stay also showed no significant association between the desflurane and sevoflurane groups.</p> Conclusions <p>Desflurane-based anesthesia was not associated with increased postoperative pulmonary complications and mortality compared to sevoflurane in patients with chronic respiratory diseases undergoing gastrointestinal cancer surgery. However, further studies using reliable diagnostic criteria to assess COPD or asthma are warranted.</p>