Background: Postoperative hyperglycemia related to stress has been shown to be an independent risk factor for periprosthetic joint infection. In a non-intensive care, general-surgery setting, a standardized postoperative insulin protocol has been shown to decrease the rate of wound infections. We hypothesized that the use of a similar protocol is both safe and effective for controlling hyperglycemia in patients who have undergone total joint replacement., Methods: We performed a retrospective cohort study of 489 consecutive patients who underwent primary or revision total hip or knee arthroplasty between January 2008 and April 2013. All patients were tested with point-of-care (finger-stick) glucose determinations postoperatively and were started on a subcutaneous insulin protocol if they had postoperative stress hyperglycemia of >140 mg/dL when fasting or >180 mg/dL after meals. Insulin was discontinued when blood glucose decreased to <100 mg/dL., Results: Of the 489 patients, 301 (62%) qualified for the insulin protocol. Thirty-seven (17%) of the 220 patients for whom the hemoglobin A1c level was available were diabetic, and 21 (11%) of the 187 patients for whom body mass index data were available were morbidly obese (body mass index, ≥40 kg/m 2 ). Diabetes (p < 0.001), revision surgery (p < 0.001), male sex (p = 0.0110), and obesity (including morbid obesity) (p = 0.0051) were independent factors resulting in significant glycemic elevation. A trend toward hyperglycemia occurred in younger patients but did not reach significance (p = 0.063). The glucose levels of patients in all of these groups responded well to insulin. None of the patients who were managed with the insulin experienced a periprosthetic joint infection. There were no injuries related to hypoglycemia., Conclusions: The findings of the present study suggest that hyperglycemia is a common link between seemingly disparate factors related to the increased prevalence of periprosthetic joint infection. The standardized subcutaneous insulin protocol was both safe and effective for the treatment of hyperglycemia for nondiabetic as well as diabetic patients. Patients who have undergone total joint replacement, especially those with revision procedures, male sex, morbid obesity, and diabetes, should be evaluated for hyperglycemia starting in the post-anesthesia care unit and should be managed with the insulin protocol when that risk is identified., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.