Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). A retrospective study was performed to evaluate the role of endothelial nitric oxide synthase (eNOS) gene polymorphisms (E298D and T-786C) in African-American SCD patients. The D298 allele showed no association; the C-786 allele showed a statistically significant association (P = 0.0061) in female ACS cases. Multiple logistic regression analysis showed that relative risk of ACS was 8.695 (P = 0.0076, 95% confidence interval 1.761-42.920) for female carriers of C-786. eNOS T-786C is a gender-specific genetic modifier that is associated with increased susceptibility to ACS in female SCD patients.