Intensive insulin therapy to maintain blood glucose at or below 6.11 mM reduces morbidity and mortality after cardiac surgery and morbidity in medical intensive care unit (ICU) patients. The authors investigated the clinical safety and outcome effects of intensive insulin therapy compared to conventional insulin therapy in patients receiving postoperative intensive care after neurosurgical procedures. In this prospective randomized controlled trial, 483 patients undergoing elective or emergency brain surgery were prospectively and randomly assigned either to intensive insulin therapy (241 patients), receiving insulin titrated to maintain blood glucose levels within the range of 4.44-6.11 mM, or to conventional insulin therapy (242 patients), receiving insulin to maintain blood glucose levels below 11.94 mM. Primary endpoint was incidence of hypoglycemia (defined as blood glucose < 2.78 mM). Efficacy measures included the length of ICU stay, infection rate, and 6 months follow-up Glasgow outcome scale score and overall survival. Hypoglycemia episodes were more frequent in patients receiving intensive insulin therapy, median (min-max): 8 (0-23) versus 3 (0-4); P < 0.0001. The length of stay in the ICU was shorter (6 vs. 8 days; P = 0.0001), and the infection rate was lower (25.7% vs. 39.3%; P = 0.0018). Glasgow outcome scale score and overall survival at 6 months were similar in the two groups. Intensive insulin therapy in patients admitted to a postoperative neurosurgical ICU after brain surgery is associated with iatrogenic hypoglycemia, but it can also reduce the infection rate and shorten the ICU stay.