Background Blood glucose control during acute illness has been associated with improved outcomes. Objectives To evaluate adherence to and efficacy and safety of an insulin protocol for critically ill patients with target blood glucose levels between 81 and 110 mg/dL and to determine factors associated with adequate daily blood glucose control. Methods In a prospective observational study, blood glucose levels were determined in 30 patients in intensive care units of a tertiary care university hospital during a 2-month period. All glucose measurements and corresponding insulin infusion rates were evaluated for adherence to and efficacy and safety of the insulin protocol. Linear regression analysis was used to determine factors associated with adequate daily blood glucose control, defined as time in the target range. Results A total of 6016 blood glucose measurements were obtained during 352 protocol implementation days. Adherence to the protocol was 71%. Blood glucose levels were in the desired range 42% of the total protocol implementation time. Sixty percent of the patients experienced at least one hypoglycemic event. Adherence to the protocol ( P < .001), high bilirubin level ( P < .001), low daily insulin dose ( P = .002), and low C-reactive protein level ( P = .048) were independently associated with adequate daily blood glucose control. Conclusions Protocol adherence was positively associated with daily time in the target range, but efficacy during the total protocol implementation time remained poor. Because of the frequency of hypoglycemia, protocols to maintain blood glucose levels between 81 and 110 mg/dL in critically ill patients may not be recommended.