We investigated the association of VEGFA -583C > T on VEGF serum levels and acute chest syndrome (ACS) in 351 pediatric patients with sickle cell disease (SCD), of whom 90 had ACS, and 261 were ACS-free controls. Significant differences in -583C > T minor allele and genotype frequencies were seen between ACS cases and controls, evidenced by enrichment of -583T/T genotypes in patients with ACS, which were linked with reduction in VEGF serum levels. VEGFA -583C > T and reduced VEGF serum levels may influence ACS risk in patients with SCD, which will aid in identifying patients with SCD who are at high risk of ACS.