Vancomycin is well recognized as causing the nonallergic skin reaction known as red man syndrome; however, it is rarely suspected as causative in the setting of an immune-mediated skin reaction. We describe a 76-year-old Caucasian woman with a history of penicillin and sulfa allergies who was transferred to our medical center while receiving vancomycin for treatment of persistent methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. After admission, the patient's pacemaker was explanted; cultures from the pacemaker grew MSSA. Based on the culture data and her allergy to penicillin, vancomycin was continued. On day 4 of therapy, the patient developed a papular rash with small blisters on her distal upper extremities. Furosemide, which she was receiving intermittently to maintain fluid balance, was initially suspected as the likely cause. Furosemide was withheld; however, the rash worsened and spread to her neck and torso. Results of skin biopsy confirmed a severe leukocytoclastic, necrotizing small-cell vasculitis that met the criteria for a hypersensitivity vasculitis associated with drug therapy. Five days after discontinuation of vancomycin, the vasculitis was resolving and continued to resolve throughout the remainder of her hospitalization. Furosemide was readministered without worsening of the vasculitis. Use of the Naranjo adverse drug reaction probability scale indicated that the likelihood of vancomycin being the cause of the vasculitis was probable (score of 5). Clinicians should be aware of vancomycin as a potential cause of small-vessel vasculitis.