Hypothermia is a dangerous adverse effect that occurs in burn patients. Hypothermia leads to decreased renal blood flow and may decrease renal clearance of medications. Few human studies examine the effect of hypothermia on drug clearance and no known studies examine its effect on vancomycin clearance in burn patients. This case report describes a 39-year-old female who suffered 60% total body surface area third-degree burns. The patient required vancomycin, empirically, and for definitive treatment of methicillin-resistant Staphylococcus aureus. During three of the vancomycin courses, the patient experienced significant hypothermia. Vancomycin concentrations obtained during normothermia were found to be subtherapeutic or therapeutic. Concentrations obtained during hypothermia were found to be supratherapeutic and rate elimination constants were found to be significantly decreased by 45, 25, and 31%, respectively. These patient data suggest that hypothermia can decrease vancomycin clearance in burn patients as evidenced by supratherapeutic vancomycin concentrations and decreased rate elimination constants. Burn patients should be monitored closely for hypothermia. If hypothermia occurs during treatment, vancomycin concentrations should be obtained frequently, even if renal function appears stable. Dosing based on concentrations may be necessary in order to avoid supratherapeutic vancomycin concentrations and associated adverse drug events.