The predominant pathophysiological feature of homozygous sickle cell anemia (SCA) is the vaso-occlusion. Vaso-occlusion can be associated with painful crises, which are the primary reason for those patients to seek medical care. Vaso-occlusion is responsible for the acute chest syndrome (ACS) with large morbidity and mortality or more rarely (and especially in adults) for priapism and acute neurological events (strokes). A 10-year-old boy with homozygous SCA was admitted to the Pediatric Emergencies with painful vaso-occlusive crisis and fever. Initially he had normal chest X-ray but, after 24-hour-hospitalization, he developed ACS with new chest X-ray findings. He was treated with broad spectrum antibiotics, blood transfusions and bronchodilators and after a six-day treatment, he was significantly improved. The patient was discharged 13 days later with no other therapy at home. The possibility of ACS development should be still considered, even when a known patient with SCA presents a painful vaso-occlusive crisis with an initial normal chest X-ray. Therefore, repeated clinical examination is required and possible changes in the clinical status could indicate the necessity of a new radiographic examination. In this way, early ACS could be recognized and the catastrophic consequences due to this syndrome could be avoided.