Hydroxyurea is an antimetabolite drug that is commonly used in many hematological disorders. Ulcer formation in the gastrointestinal tract is a rare phenomenon associated with this drug. We report a case of a 73-year-old woman who was found to have an isolated ileocecal valve ulcer while on hydroxyurea 1 g daily for essential thrombocythemia. A comprehensive evaluation ruled out all other causes. The cytoreductive therapy was switched to anagrelide and the endoscopic evaluation 6 months later showed complete healing of the ulcer. However, the hydroxyurea was resumed due to increasing platelet counts and intolerance to dose increments of the anagrelide. Subsequently, the patient was found to have a recurrence of the ulcer. Apart from oral ulcers, there have also been reports of ulcers involving the small bowel and the colon associated with the use of hydroxyurea. The pathophysiology of the non-oral gastrointestinal ulceration in relation to this drug is unclear. Withdrawal of the drug typically leads to complete resolution. Increasing awareness of the rare association between the use of hydroxyurea and nonoral gastrointestinal ulcers is essential for early detection to prevent related complications.