Apolipoprotein A1 (apoA1) is the major apoprotein constituent of high density lipoprotein (HDL) which exerts innate protective effects in systemic inflammation. However, its role in the acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) has not been well studied. The objective of this study was to investigate the potential association between APOA1 -75 G/A polymorphism and the development of ALI after cardiopulmonary bypass (CPB) surgery.A hospital-based case-control study was conducted in patients with ALI (n = 300), patients without ALI (n = 300) and healthy controls (n = 300). Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess the APOA1 -75 G/A genotypes.Patients with ALI had a significantly higher frequency of APOA1 -75 AA genotype [odds ratio (OR) =1.75, 95% confidence interval (CI) = 1.04, 2.92; P = 0.03] than patients without ALI. APOA1 -75 AA genotype (OR =3.47, 95% CI = 1.60, 7.52; P = 0.002) and A allele (OR =1.92, 95% CI = 1.24, 2.96; P = 0.003) were the significant independent prognostic factors for the 30-day survival rate of patients with ALI after CPB surgery.Our study suggested that APOA1 -75 AA genotype was associated with a higher ALI risk after CPB surgery. Patients with the APOA1 -75 AA genotype and A allele had higher 30-day mortality of ALI after CPB surgery. Additional studies are needed to confirm this finding.