Acute Chest Syndrome (ACS) describes a syndrome characterized by the presence of a new pulmonary infiltrate on a chest X-ray, fever, and respiratory symptoms and is the leading cause of death and hospitalization in sickle cell disease (SCD). We studied 21 patients affected by SCD (13 HbSbeta+, 4 HbS beta(o), 4 HbSS, mean age 38.2 years). Six out of the 21 patients developed one episode of ACS (two patients had positive blood cultures, for Mycoplasma pneumoniae and Haemophilus influenzae respectively). The aim of our study was to evaluate the therapeutic efficacy of red cell-exchange during ACS. This procedure decreases HbS levels. The patients who underwent erythro-exchange showed a dramatic clinical and radiographic improvement with stabilized HbS levels between 20% and 30%. During follow up (14-32 months), none of the 6 patients developed viral complications related to transfusion therapy, alloimmunization or recurrence of ACS. In conclusion, in regard to the pre- and post-red cell-exchange clinical and laboratory data, we can say that red cell-exchange provides a dramatic resolution of the episode of ACS, minimizes the development of iron overload, and rapidly decreases HbS and hematocrit levels. In light of our results, we hypothesize that ACS episodes are secondary to pulmonary damage and to a gradual worsening related to age, and that there is some evidence that individuals affected by SCD in the third to fourth decade of life are more susceptible to ACS and/or other severe disease-related complications, needing repeated and strict clinical follow up.