Background and objectives: The aim of this prospective, observational study was to evaluate changes in regional cerebral oxygen saturation (rSO2) and incidence of intraoperative cerebral desaturation in a cohort of elderly patients undergoing major abdominal surgery. Methods: rSO2 was continuously monitored on the left and right sides of the forehead in 60 patients older than 65 yr (35 males and 25 females; ASA II–III; age: 72 ± 5 yr; without pre-existing cerebral pathology, and baseline Mini Mental State Examination (MMSE) score >23) undergoing sevoflurane anaesthesia for major abdominal, non-vascular surgery >2 h. Results: Baseline rSO2 was 63 ± 8%; cerebral desaturation (rSO2 decrease <75% of baseline or <80% in case of baseline rSO2 <50%) occurred in 16 patients (26%). The MMSE decreased from 28 ± 1 before surgery to 27 ± 2 on 7th postoperative day (P = 0.05). A decline in cognitive function (decrease in MMSE score ≥ 2 points one week after surgery as compared to baseline value) was observed in six patients without intraoperative cerebral desaturation (13.6%) and six patients who had intraoperative cerebral desaturation (40%) (P = 0.057) (odds ratio: 4.22; CI95%: 1.1–16). Median (range) hospital stay was 14 (5–41) days in patients with an area under the curve of rSO2 <50% (AUCrSO2<50%) >10 min%, and 10 (4–30) days in those with an AUCrSO2<50% <10 min% (P = 0.0005). Conclusions: In a population of healthy elderly patients, undergoing non-vascular abdominal surgery cerebral desaturation can occur in up to one in every four patients, and the occurrence of cerebral desaturation is associated with a higher incidence of early postoperative cognitive decline and longer hospital stay.