One hundred ninety-five older patients undergoing elective joint replacement were randomized to receive either 40 IU of intranasal insulin twice daily (n=96) or placebo (n=99) for 8 days surrounding surgery. The primary outcome was the incidence and severity of postoperative delirium (POD) assessed using the Confusion Assessment Method and Delirium Rating Scale-98 over the first 5 days postoperatively. Secondary outcomes included insulin sensitivity (via HOMA-IR), and levels of total and uncarboxylated osteocalcin and brain-derived neurotrophic factor (BDNF) in plasma and cerebrospinal fluid. Overall, the results of the study revealed that intranasal insulin significantly lowered the incidence and severity of POD compared to placebo, while also improving peripheral insulin sensitivity and increasing osteocalcin and BDNF levels. These findings suggest intranasal insulin may serve as an effective intervention to reduce postoperative delirium in older surgical patients, potentially by modulating neuroendocrine biomarkers.