Hydroxyurea is an antimetabolite that is widely used in the treatment of many benign and malignant conditions. This drug is usually well tolerated but has a number of side effects that vary in incidence. In cases of clinically significant adverse events, hydroxyurea is usually discontinued either temporarily or permanently, depending on treatment need versus harm caused by side effects. Here, we report a case of oral ulceration associated with hydroxyurea treatment in a patient who had chronic myelogenous leukemia. The patient rapidly developed an oral ulcer 12 days after administration of the drug. Hydroxyurea was discontinued, and the oral lesion appreciably decreased in size and severity. Physicians and dentists should be aware of the association between hydroxyurea and oral lesions.