The activation and recruitment of neutrophil cells in lung tissue are the characteristic features of acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Interleukin 18 (IL-18) is a potent activator and inducer of accumulating neutrophils in lung, and higher IL-18 level has been shown to link to IL-18 gene -607C/C genotype. Therefore, the polymorphisms in IL-18 gene promoter were examined to investigate the association with susceptibility to the development of ALI after cardiopulmonary bypass (CPB) surgery in this study. The results showed the significant involvement of -607C/ genotype in patients with ALI (n = 18, 18/43, 41.9%) compared with those patients without ALI (n = 32, 32/155, 20.6%, P = 0.0037) and healthy controls (n = 198, 53/198, 26.8%, P = 0.06). The frequencies of -607C/C,C/A,A/A genotypes were 41.9%, 46.5%, and 11.6% in patients with ALI and 20.6%, 47.1%, and 32.3% in patients without ALI. The allelic frequency of C (65.1%) was significantly higher in patients with ALI than that of patients without ALI (44.2%) [odds ratio(OR) = 0.42, 95% confidence interval (CI) = 0.26 - 0.70; P = 0.0006]. No significant association of -137 polymorphism with susceptibility of ALI was found. There were no significant differences between the patients who had undergone CPB operation and healthy controls. In conclusion, our findings suggest that -607C/C genotype in IL-18 gene plays a pivotal role in the development of ALI after CPB surgery in Chinese Han population.