Hydroxyurea is an established drug that has been used for the treatment of myeloproliferative disorders and some solid tumors for some time. In recent years it has also been found to be effective in the treatment of sickle cell disease. Short term side effects are not serious, and are manageable. The major concern is the potential leukemogenesis with long term use. The risk of leukemogenesis is not defined with its use in benign hematological conditions. We report a case of acute myeloid leukemia with no preceding myelodysplastic syndrome, occurring after 2 years of hydroxyurea therapy in a patient with sickle cell disease.