We describe a case of intraoperative anaphylaxis resulting from isosulfan blue (IB) dye, an agent being increasingly used for identification of sentinel lymph nodes. A 45-year-old woman undergoing a left mastectomy with sentinel lymph node biopsy under general endotracheal anesthesia developed severe intraoperative hypotension and tachycardia 10 minutes after subcutaneous injection of IB dye for lymphatic mapping. This was associated with a reduction in pulse oximeter reading to 89%. She was successfully resuscitated using 1 mg of epinephrine intravenously (IV). Invasive arterial and central venous pressures were initiated; her lymph node biopsy was concluded, but the rest of her procedure was canceled. Postoperative workup revealed a high tryptase level indicative of an intraoperative anaphylactic reaction most probably related to the IB dye. Isosulfan blue dye can act as an antigen, causing a full-blown intraoperative anaphylactic reaction. Early recognition and aggressive hemodynamic interventions can reduce morbidity and mortality.