Omeprazole is a proton pump inhibitor (PPI) that is indicated for gastroduodenal ulcer, gastroesophageal reflux and hypersecretory states. It has an excellent safety profile with a low incidence of adverse effects. We report an Omeprazole-induced urticaria in a patient and emphasize the role of allergological work-up to point out the culprit drug and in exploring cross-reactivity. A 56-year-old man with a history of Biermer anemia treated by vitamin B12. He has asthma and no other illnesses, allergic diseases or reactions, especially to drugs. He was treated with Omeprazole, for abdominal discomfort. Four hours after the first dose, the patient developed urticarial lesions with annular erythematous wheals localized on the trunk and upper limbs. There was neither angioedema nor respiratory and hemodynamic symptoms. An acute generalized urticaria to omeprazole was suspected. Four weeks later, Skin prick test than intradermal tests (IDT) to omeprazole were performed on the patient’s forearm. They revealed respectively a negative and a positive result. To assess cross-reactivity to other PPIs in our patient, we subsequently performed prick test to lansoprazole and IDT to esomeprazole, and pantoprazole that were negative at 20-min reading. Moreover, graded oral provocation test with these drugs were carried out with negative result. In conclusion we add to the medical literature a case report of omeprazole-induced urticaria without a cross reactivity and point out the usefulness and safety of skin and provocation testing in diagnosing this drug reaction and in the assessment of cross-reactivity between PPIs. KEYWORDS: omeprazole, urticaria, cross-reactivity, selective hypersensitivity