<h3>Introduction</h3> Proton pump inhibitors (PPIs) are widely used inhibitors of gastric acid secretion. PPIs are generally well tolerated with very few side effects and hypersensitivity reactions are rarely described. Here we present an adult man who reports anaphylaxis upon treatment with oral omeprazole. <h3>Case Description</h3> A 56-year-old man presented with symptoms of skin rash with pruritus of the skin upon treatment with oral omeprazole in treating Helicobacter pylori on two separate occasions. The reaction occurred after the first dose of the drug. Allergy skin testing (SKT) to pantoprazole was negative, and the patient tolerated the graded oral challenge to Pantoprazole. To treat the H. pylori infection, the patient took Talicia (amoxicillin, rifabutin, and omeprazole) and developed generalized pruritus, itchy tongue, throat, and bilateral hand swelling within 20 minutes of taking this medication. He also experienced chest tightness, shortness of breath, abdominal pain, dizziness, and vomiting. The patient was taken to the emergency department and received IV Benadryl (25 mg), famotidine (20 mg), methylprednisolone (125 mg), and intravenous fluids (1L NS), with an improvement in his symptoms. Upon follow-up for this anaphylactic reaction, allergy SKT and challenge to penicillin were performed which were negative. <h3>Discussion</h3> This case reinforces the importance of performing SKTs and oral drug challenges for each medication within the PPI drug class. The cross-reactivity between different PPIs is not currently well described, and other PPIs should be avoided unless an SKT and oral drug challenge are performed under close observation. Further studies are needed to provide more information on cross-reactivity among PPIs.