Omeprazole is a substituted benzimidazole that has gained widespread use in the treatment of acidic and peptic ulcer disease. Adverse events with the drug are rare and involve mainly the gastrointestinal and central nervous systems. Skin inflammation, urticaria, pruritus, alopecia, and dry skin have been reported in 0.5-1.5% of patients. To date, no published report has linked angioedema with omeprazole. We report a case of a 34-year-old woman with cellulitis, ulcerative erosive esophagitis, and gastric and duodenal ulcers who developed several hypersensitivity reactions characterized by shortness of breath, wheezing, cough, mild angioedema, and total body urticaria and pruritus. These symptoms correlated with the addition of omeprazole to her regimen and the timing of its administration. A previous case report prompted a rechallenge with enteric-coated omeprazole granules removed from the capsule shell. Recurrence of the adverse events suggested an allergy to the drug itself and not the capsule. Angioedema can be a life-threatening allergic reaction requiring immediate treatment. Rechallenge using omeprazole with or without the capsule shell should be done only in a hospital setting where prompt action can be taken in the event of an emergency.