ObjectiveStudies of genetic associations with common diseases, such as between cytokine gene polymorphisms and severe bacterial sepsis, have reached conflicting conclusions. Failure to follow methodologic standards may have contributed to discordant findings. The −308 G→A transition in the tumor necrosis factor-&agr; promoter has been genotyped by a variety of methods. Based on our observation of genotyping inaccuracies, we sought to determine whether published studies followed a series of acceptable methodologic standards and whether failure to follow the standard of genotyping reproducibility could lead to erroneous conclusions about gene-disease associations.DesignSystematic review and reanalysis of banked genetic material. We applied a published series of seven methodologic standards to five reports of the association between this variant and bacterial sepsis. We then studied the accuracy of restriction fragment length polymorphism for the −308 site using DNA from a cohort of injury victims.SettingSurgery research laboratory.Measurements and Main ResultsWe observed that methodologic quality was not uniform and that reproducibility of genotyping was infrequently met. In our subjects, we found that 4 of 46 heterozygotes analyzed by restriction fragment length polymorphism were actually GG-homozygotes (9% misclassified) according to alternative genotyping methods.ConclusionsFailure to confirm genotype may have led to conclusions that this polymorphism is not associated with sepsis or outcome. Our observations have implications for the conduct and evaluation of studies of complex genetic disease.