Background <p>Perioperative neurocognitive disorders (PND), encompassing postoperative delirium (POD), delayed neurocognitive recovery (dNCR), and postoperative neurocognitive disorder (postoperative NCD), are commom complications of surgery in older adults. Urological surgery carries particularly high risk, with reported incidences reaching 30%. Elevated serum biomarkers in affected patients suggest diagnostic and prognostic utility. Although propofol may reduce postoperative neurocognitive disorder risk compared with other inhalational agents, data on desflurane remain limited despite its rapid pharmacokinetics. This study compared the incidence of POD, dNCR, postoperative NCD, perioperative complications, and biomarker profiles in patients receiving general anesthesia with propofol or desflurane.</p> Methods <p>This prospective randomized controlled trial enrolled patients aged 65 years or older undergoing major urological surgery, who were assigned to receive propofol (via target-controlled infusion) or desflurane. Anesthesia depth and cerebral oxygenation were maintained using bispectral index monitoring (40–60) and near-infrared spectroscopy (≥ 60%), respectively. Serum biomarkers were measured at 5 time points (T0–T4). POD was assessed on postoperative days 1–3 using the 3-Minute Diagnostic Interview for Confusion Assessment Method, whereas dNCR and postoperative NCD were assessed using the Montreal Cognitive Assessment between postoperative days 5–9 and at 3–6 months postoperatively, respectively.</p> Results <p>Among 126 patients (propofol, 64; desflurane, 62), overall POD incidence was 14.1% versus 9.8% (<i>P</i> = 0.467), and dNCR incidence at days 5 through 9 was 4.7% versus 11.5% (<i>P</i> = 0.199). However, the number of delirium-present days was statistically significantly greater in the desflurane group (1 [1–1] vs. 1.5 [1–2]; <i>P</i> = 0.044). Interleukin-6 levels increased substantially in both groups, with higher levels on day 3 in patients with POD than in those without (63.8 [42.9–206.4] vs. 31.2 [20.9–69.8] pg/mL; <i>P</i> = 0.009).</p> Conclusions <p>Although PND incidence did not differ between propofol and desflurane, delirium duration was longer with desflurane; however, this exploratory finding should be interpreted cautiously given the small number of delirium cases. Interleukin-6 may serve as a useful biomarker for POD monitoring. Bispectral index and near-infrared spectroscopy-guided anesthesia management may help reduce the incidence of PND.</p> Trial registration <p>This study was registered in the Thai Clinical Trials Registry on 24/09/2021 (registration number: TCTR20210924002).</p>