Background: Glycemic control using intravenous insulin infusions is an important component of hyperglycemic crisis treatment. Literature supports the use of standardized titration protocols; however, comparisons of specific methods are limited. Objective: Compare the safety and efficacy of 2 insulin infusion titration methods used in hyperglycemic crisis. Methods: A retrospective chart review was conducted including adults admitted to an inpatient facility from August 1, 2013, to August 1, 2015, who were treated for at least 4 hours with an intravenous insulin infusion. Primary efficacy outcomes of time to anion gap closure and time to goal blood glucose was studied in patients meeting criteria for diabetic ketoacidosis (n = 79), while the primary safety outcome of rates of hypoglycemia were compared among all study patients (n = 200). Results: The fixed-rate titration method had statistically shorter time to blood glucose <200 mg/dL compared to the multiplier titration group (6.1 [4.0] vs 8.8 [4.4], respectively; P = .018; mean time in hours [standard deviation]); however, no statistically significant difference was seen in the other primary efficacy and safety outcomes. Statistical improvements were found in secondary outcomes of intensive/progressive care units, length of stay, and infusion duration in the fixed-rate titration method, while less deviation from titration recommendations was found in the multiplier titration group. Conclusions: Significant differences seen in time to a goal blood glucose, deviation prevalence, and holds of the infusion for low blood glucose have identified areas for optimization, additional study, and staff education.