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Experimental and clinical studies support the key role of interleukin 6 (IL-6), a potent proinflammatory cytokine, in the development of acute lung injury (ALI). Plasma IL-6 levels are influenced mainly by genetic determinants, and a −174G/C polymorphism of the gene has been recently associated with susceptibility to ALI. Here we aimed to validate the association of theIL6gene with ALI in a case-control sample from Spain. DNA was isolated from 67 consecutive patients who fulfilled international criteria for severe sepsis and for ALI and 96 population-based controls drawn from the general population. Genotypes of the −174G/C polymorphism along with other 14 tagging variants of theIL6gene were evaluated. Twenty polymorphisms unlinked toIL6gene were additionally compared between cases and controls to rule out population stratification. None of the individual single-nucleotide polymorphisms was significantly associated with susceptibility to ALI. However, we found that a common haplotype from −1363 to +4835 from the transcription start site, and spanning the gene, conferred risk for susceptibility to ALI (odds ratio, 2.73; 95% confidence interval, 1.39-5.37;P= 0.003). Adjustment for relevant covariates did not modify this result. These data support the association of theIL6gene with ALI susceptibility and illustrate the value of haplotype analysis as a robust approach for evaluatingIL6gene effects in association studies.