Background <p>The effects of inhalation anesthesia as compared with total intravenous anesthesia (TIVA) on postoperative recovery quality in patients undergoing transsphenoidal resection of pituitary adenoma have not been well studied.</p> Methods <p>This randomized clinical trial enrolled patients undergoing transsphenoidal surgery between May 2023 to April 2024. Patients were randomly assigned in a 1:1 ratio to receive inhalation anesthesia or TIVA. The primary endpoint was the 15-item Quality of Recovery Scale (QoR-15) score on the first postoperative day. Secondary endpoints included postoperative anesthesia recovery patterns, neuroendocrine stress responses, cellular immune responses, and recovery quality. Subgroup analyses were also conducted for the postoperative QoR-15 scores and neuroendocrine stress responses. Potential influence factors for QoR-15 scores and changes in counts of lymphocytes were explored.</p> Results <p>A total of 252 patients were randomized. No significant difference in postoperative QoR-15 scores was observed between groups and the between-group difference was well below the minimal clinically important difference (median difference 1.0, 95% confidence interval [CI]– 4.0 to 5.0, <i>P</i> = 0.647). Compared with the inhalation group, the TIVA group exhibited significantly lower Richmond agitation-sedation scale (RASS) score and reduced antiemetic drug use in the postanesthesia care unit. Subgroup analyses for postoperative QoR-15 scores revealed no significant interactions. Adrenocorticotropic hormone levels on postoperative day 1 were lower in the inhalation group, while thyroxine and serum free thyroxine levels were higher. No significant differences in these neuroendocrine indices were found in postoperative month 3. Lymphocyte subset levels did not differ between groups on postoperative day 1, although perioperative changes in immune cell counts were correlated with patient demographic and clinical characteristics.</p> Conclusion <p>Both anesthesia methods resulted in comparable short-term postoperative recovery quality as measured by the QoR-15 scores. TIVA was associated with smoother anesthesia recovery and lower immediate antiemetic requirements. Differences in early neuroendocrine responses were observed but did not persist at 3 months postoperatively.</p> Trial registration <p>The trial is registered with the ClinicalTrials.gov platform (registration number: NCT05822817; date of registration: March 13, 2023).</p>