Kikuchi-Fugimoto's Disease (KFD), also known as histiocytic necrotizing lymphadenitis, is most frequently seen in young women and has been associated with autoimmune disorders such as polymyositis and systemic lupus erythematosus. It is generally a self-limiting disease with recovery time ranging from weeks to months. A typical presentation of KFD includes painful cervical lymphadenopathy, usually consisting of unilateral involvement of the posterior cervical chain. To date, this condition has not been described in patients with sickle cell disease. We present 2 cases of KFD, 1 in a patient with sickle beta(o)-thalassemia (Sbeta(o)thal) and 1 in a patient with sickle cell anemia with hereditary persistence of fetal hemoglobin (HbS-HPFH). Both patients were young-adult African American females who presented with fever and unilateral tender cervical lymphadenopathy. Extensive infectious disease testing, including cultures and viral serologies, were all negative. Imaging was negative for abscesses. The first patient had a preceding history of benign carcinoid tumor and idiopathic thrombocytopenic purpura. The second patient had no history of autoimmune syndromes but was on hydroxyurea therapy at the time of her presentation; the first had never taken hydroxyurea. Treatment strategies included prednisone therapy in the first case and watchful monitoring in the second. Recovery time was approximately 2 months for each patient. Both developed thyroid disease subsequent to their episode of KFD. Currently, both patients are asymptomatic with no recurrence of KFD or active autoimmune disease.