A 33-year-old, 50-kg female with end-stage renal disease (ESRD) secondary to reflux nephropathy was scheduled for a zero-mismatch cadaveric renal transplant. She was dependent on peritoneal dialysis, and her past medical history was also notable for anemia and secondary hyperparathyroidism. She was on multiple antihypertensive medications, and she reported no drug allergies, which was also confirmed with a review of the medical record. Notably, however, she did verbalize a reaction to an unknown sedative that she received for a procedure in 2019 that resulted in the sole symptom of pruritus in her lower extremities. Aside from this reaction, she had several previous general anesthetics that had been uncomplicated and had received cefazolin twice in the past without adverse reactions. The patient was hypertensive before induction of anesthesia with systolic blood pressure (SBP) range from 170 s to 200 mmHg and a diastolic blood pressure (DBP) range from 95 to 110 mmHg. Her heart rate was normal in the 70 s and oxygen saturation was greater than 95%. Induction of anesthesia was achieved with propofol and cisatracurium, and anesthesia was maintained with sevoflurane. The lowest blood pressure reading during and after induction was 137/89 mmHg, and the patient state index (PSI) on SedLine was between 10 and 30. The routine peri-transplant immunosuppressive dose of methylprednisolone (total 500 mg) was started 12 min after induction and given over 25 min. A routine bolus of cefazolin (2 g) was given intravenously (IV) over 3 min prior to incision. The surgical team made the incision, and 4 min following the administration of cefazolin, the blood pressure decreased from 140/80 to 75/44 mmHg. No bronchospasm or mucocutaneous signs were appreciated. However, tachycardia, hypotension, and cardiovascular collapse were observed. In addition, the pleth variability index (PVI) increased significantly from 4 to 14, and PSI remained between 20 and 30. She was initially treated with phenylephrine. She was not responsive to the phenylephrine and received epinephrine (total 100 mcg). The hypotension worsened (55/45 mmHg), she had bradycardia in the 50 s, oxygen saturation in the 70 s, and the femoral pulse was not palpable. Sevoflurane and methylprednisolone were both discontinued. The SedLine raw electroencephalogram did not display burst suppression, and PSI was between 20 and 30. The five-lead electrocardiogram was assessed, and no changes were noted. The ventilator showed normal peak pressures, and the capnograph waveform shape was normal. The end-tidal carbon dioxide (ETCO2) had decreased from the high 30 s to the low 20 s. The patient’s skin and oral mucosa appeared normal and the lungs were clear bilaterally. The patient was given 1.5 mg of epinephrine followed by 18 units of vasopressin to achieve hemodynamic stability. Within 7 min, hemodynamics improved to baseline. The delivery of sevoflurane was resumed, with the highest PSI noted to be 43. A tryptase level was sent. A discussion was held about whether or not to proceed with the planned surgical procedure. The patient was observed for approximately 20 min during which she remained stable. The decision was made to proceed with the kidney transplant due to the excellent immunologic matching between the donor and recipient (zero antigen mismatch). The surgical procedure was resumed, and the patient remained stable for the rest of the case without the need for additional vasopressors or inotropes. She was admitted to the intensive care unit (ICU) for observation secondary to presumed intraoperative anaphylaxis and a near cardiopulmonary arrest. Her ICU admission was uncomplicated except for the need for oral midodrine on postoperative day 1, which she received to achieve a mean arterial pressure (MAP) goal of > 70 to provide adequate perfusion to the renal allograft. On postoperative day 2, the MAPs ranged in the 80–100 s and midodrine was discontinued. The patient was transferred out of the ICU. She had excellent early graft function and her laboratory results were as expected until discharge on post-operative day 4. Her intraoperative tryptase level was elevated at 51.8 mcg/L (normal < 11 mcg/L), and 1 month following surgery returned to normal (5.5 mcg/L). As part of her intraoperative anaphylaxis work-up, the patient was seen in the Allergy and Immunology Clinic for skin prick testing of multiple agents she had been exposed to intraoperatively. Propofol, penicillin, and amoxicillin skin testing were negative. Methylprednisolone was initially considered as a potential etiologic agent, but since she received large doses subsequently on postoperative days 1 and 2 without any reaction it was excluded. Latex and chlorhexidine were not considered likely culprits given the lack of their temporal relationship between exposure and reaction. The cefazolin skin testing was positive, suggesting that cefazolin was the likely cause of her intraoperative anaphylactic episode.