Mycoplasma pneumoniae, which usually causes mild infections in normal children, has been shown to cause isolated cases of severe pneumonia in children with sickle cell disease. We recently observed an outbreak of Mycoplasma pneumonia in three sisters with homozygous sickle cell disease. Two of them required hospitalization, and one progressed to respiratory failure requiring prolonged ventilatory assistance. All eventually recovered without long-term pulmonary complications. Familial outbreaks are not uncommon in Mycoplasma infection, but they have not been described previously in siblings with sickle cell disease. It is assumed that local or systemic host defense abnormalities predispose patients with sickling syndromes to more severe courses of Mycoplasma infections.