The role of cytokines in the development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) was studied. Serum interleukin 8 (IL‐8) levels were elevated in 14 episodes and undetectable in six out of 20 episodes of ACS in 19 patients with SCD. In contrast, IL‐8 levels were undetectable in the sera of 29 control patients with SCD studied during routine clinic visits or hospitalization for vaso‐occlusive crises. The differences in mean IL‐8 levels and the proportion of patients with detectable levels between the two groups were highly significant (P < 0·0001 and 0·04 respectively). The mean IL‐8 level in bronchial fluid samples from children with ACS was also significantly higher than that in sickle cell patients undergoing elective surgery (5500 ± 1400 pg/ml vs. 1900 ± 470 pg/ml, P = 0·03). Granulocyte colony‐stimulating factor (G‐CSF) (2000 ± 1700 pg/ml) was present in five out of six samples of bronchial fluid, but not serum, from children with ACS. All but one of the patients with ACS studied were negative for the Duffy red cell antigen, which is a receptor that binds and inactivates IL‐8 and other chemokines. These findings suggest that IL‐8 and G‐CSF may play a role in the development of the ACS and the complications associated with it.