<h3>Introduction</h3> Fosaprepitant is a small molecule, intravenously administered antiemetic drug that is a selective NK-1 receptor antagonist. Systemic hypersensitivity reactions to fosaprepitant are rare. <h3>Case Description</h3> A 42-year-old male with Shwachman-Diamond syndrome presents with newly diagnosed myelodysplastic syndrome. He was initiated on chemotherapy with azacitidine and venetoclax. He developed neutropenic fever from a perianal abscess and fistula. Chemotherapy was paused, and cefepime/metronidazole was started. When chemotherapy was restarted, he was pretreated with fosaprepitant 150mg for refractory nausea. Fosaprepitant was administered over 7 minutes. Symptoms of shortness of breath and epigastric pain began during the infusion. Hypoxia developed 17 minutes after the infusion with O2 84% and a new 4L oxygen requirement. Notable signs included wheezing, periorbital/perioral edema, tachypnea, and tachycardia. He received 0.3mg IM epinephrine, nebulized epinephrine, 50mg IV Benadryl, and 125mg IV methylprednisolone. He required intubation for worsening upper lip/tongue edema and recrudescence of wheezing as well as an epinephrine IV infusion for hypotension. A tryptase level was drawn 3 hours after symptom onset and was elevated to 13.2 mcg/L (baseline 6.7 mcg/L). <h3>Discussion</h3> Fosaprepitant is an unusual cause of systemic hypersensitivity reactions with <1% incidence reported in the literature. Our patient represents an unexpected case of anaphylaxis on first exposure to fosaprepitant with the likely mechanism being non-IgE mediated mast cell activation. Chemotherapy and antibiotics were reintroduced without complication. Increased awareness of hypersensitivity reactions to fosaprepitant is critical given the growing use of this antiemetic drug for cases of refractory nausea.