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Hydroxyurea was approved by the Food and Drug Administration for the treatment of adults with moderate to severe sickle cell anemia and sickle-β0-thalassemia. Its major side effect is myelotoxicity, which is reversible upon discontinuation of the drug. Other side effects that have been described in animal studies but unconfirmed in humans include its teratogenic and carcinogenic potential. Additionally, hydroxyurea has idiosyncratic side effects that occur in some individuals and this may be a genetic or epigenetic phenomenon. We report three idiosyncratic side effects of hydroxyurea in four patients with sickle cell anemia (SS). Desquamating rash, decreased libido and partial complex seizures have not been previously described in patients who are hydroxyurea responders. Although these reactions are rare, they can be serious in some patients.