OBJECTIVES: Evaluate the impact of a tight glucose control (TGC) protocol during the first week of admission in critically injured trauma patients. METHODS: A prospective quasi-experimental interrupted time-series design was used to evaluate the impact of TGC [24-month preintervention phase (no TGC) vs. 24-month postintervention phase]. Patients were stratified by serum glucose level on day 1 to 7 (low, 0-150 mg/dL; medium-high, 151-219 mg/dL; and high, ≥220 mg/dL), age, gender, and injury severity. Patients were further stratified by pattern of glucose control (all low, all medium high, all high, improving, worsening, highly variable). Outcome was measured by ventilator days, infection, hospital (HLOS) and ICU (ILOS) length of stay, and mortality. RESULTS: One thousand twenty-one patients were evaluated in the preintervention phase as compared with 1108 patients in the postintervention phase. There was no significant difference in mechanism of injury (83% vs. 84% blunt), gender (74% vs. 73% male), age (44 vs. 43 years), and Injury Severity Score (ISS) (26 vs. 25). The TGC group was more likely to be in the all low and improving pattern of glucose control (P < 0.001). The incidence of infection significantly decreased (over the first 2 weeks) from 29% to 21% in the TGC group (P < 0.001). Ventilator days (OR = 3.9, 1.8, 8.1), ILOS (OR = 4.3, 2.1, 7.5), and HLOS (OR = 5.5, 2.2, 11) and mortality (OR = 1.4, 1.1, 10) were significantly higher in the non-TGC group when controlled for age, ISS, obesity, and diabetes (P < 0.01). CONCLUSION: The positive outcomes associated with the implementation of a TGC protocol necessitates further evaluation in a randomized prospective trial.