Early prediction of hypothalamic-pituitary-adrenal (HPA) axis function following transsphenoidal surgery (TSS) can improve patient safety and reduce costs. Systematic measurement of ACTH and cortisol at extubation following anesthesia to predict remission from Cushing's disease (CD) and HPA axis preservation following non-CD surgery. Retrospective analysis of clinical data between August 2015 and May 2022. Referral center. Consecutive patients (n = 129) undergoing TSS who had perioperative ACTH and cortisol measurements. ACTH and cortisol measurement at extubation. Further serial 6-hourly measurements in CD patients. Prediction of future HPA axis status based on ACTH/cortisol at extubation. ACTH and cortisol increased sharply in all patients at extubation. CD patients (n = 101) had lower ACTH values than non-CD patients (110.1 vs 293.1 pg/mL; P < 0.01). In non-CD patients, lower plasma ACTH at extubation predicted the need for eventual corticosteroid replacement (105.8 vs 449.1 pg/mL, P < 0.01). In CD patients, the peak post-extubation cortisol at 6 hours was a robust predictor for nonremission (60.7 vs 219.2 µg/dL, P = 0.03). However, normalized early postoperative value (NEPV; the post-extubation values minus the peak preoperative CRH or desmopressin test values) of cortisol reliably distinguished nonremission earlier, at the time of extubation (-6.1 vs 5.9, P = 0.01), and later. We found that at extubation following TSS, ACTH can predict the need for eventual steroid replacement in non-Cushing's patients. In patients with CD, we found a robust prediction of nonremission with NEPV cortisol at extubation and later.