OBJECTIVES: While infectious disease societies recommend weight-based loading doses of 25-30 mg/kg in critically ill patients, published meta-analyses describe increased vancomycin related nephrotoxicity at these doses. Our objective was to assess incidence of nephrotoxicity with vancomycin in emergency department (ED) sepsis patients when compliant with these recommendations. METHODS:  This was a retrospective cohort study performed in three EDs. An electronic health record (EHR)-based clinical decision support tool provided guidance at the point of order for IV vancomycin compliant with recommendations. Inclusion criteria: age ≥ 18 years, IV vancomycin order, and hospital admission. Exclusion criteria: no documented weight, hemodialysis-dependent, or < 2 creatinine (Cr) values. The primary outcome was incidence of nephrotoxicity within 5 days defined as at least 2 serial Cr higher than the initial measurement by at least 0.5 mg/dL or 50% increase. The secondary outcome was acute kidney injury (AKI) within 5 days, defined as any single increase in Cr by 0.5mg/dL or 50%. Analyses compared the incidence of nephrotoxicity and AKI between patients who received high dose (>20 mg/kg) versus low dose (≤20 mg/kg). Parametric data were compared using the t-test and categorical data with chi-squared tests. RESULTS: An EHR-based query identified 2131 consecutive patients prescribed IV vancomycin over 6 months. Of these, 1330 patients met study criteria for the primary outcome and 1631 patients met criteria for the secondary outcome. Nephrotoxicity occurred in 8% of patients. High dose vancomcyin was associated with a lower rate of nephrotoxicity (6% vs 11%, p<0.05) and a lower rate of AKI (8% vs 13%, p<0.05). CONCLUSIONS: Initial dosing of vancomycin >20 mg/kg according to guidelines was associated with a decreased rate of nephrotoxicity compared with low doses. Future analyses should distinguish between the occurrence of nephrotoxicity due to disease progression in severe sepsis versus vancomycin exposure.