Acute chest syndrome (ACS) is a new pulmonic process in a clinically ill patient with sickle cell disease. We prospectively analyzed 102 episodes of ACS in patients in our hospital during a 2-year period to study cause and clinical correlates. In 12% of the episodes, ACS was judged to be secondary to bacterial pneumonia (including only 3% secondary to Streptococcus pneumoniae), 8% was associated with uncomplicated viral pneumonias, and 16% with mycoplasmal pneumonias. The clinical course and seasonal variations in these groups were compared with those in the remaining 64% of episodes. In comparison with episodes of ACS of undetermined origin (presumably secondary to pulmonary infarct, atelectasis, or missed infections), patients with bacterial pneumonia were sicker, as shown by fever and hospitalization of longer duration, the percent of those requiring red blood cell transfusion, and the presence of pleural effusions. The lower incidence of bacterial pneumonias among our patients compared with that previously reported may reflect our use of penicillin prophylaxis and pneumococcal immunization to prevent S. pneumoniae infections.