A 24-year-old patient with homozygous sickle cell disease developed a stress fracture of the femur. Successive x-rays demonstrated defective ossification and a spontaneous unicortical fracture with no notion of trauma or stressful activities (e.g. sports) followed six months later by a bicortical fracture with displacement and periosteal reaction leading to the diagnosis of stress fracture. This type of fracture has not been reported previously in sickle cell disease. The patient was treated with centromedullary nailing. The follow-up was uneventful. Bone healing was achieved at three months. The patient was pain free and could walk without crutches. Stress fracture is a potential diagnosis in homozygous sickle cell disease patients with defective ossification who present spontaneous pain even when plain x-rays do not visualize an overt fracture. Computed tomography or magnetic resonance imaging should be performed when available. Conventional treatment with nailing provides successful cure with good functional outcome.