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<p>Abstract</p> <p>Background</p> <p>The <it>TNF</it>/<it>LTA </it>locus has been a long-standing T2D candidate gene. Several studies have examined association of <it>TNF</it>/<it>LTA </it>SNPs with T2D but the majority have been small-scale and produced no convincing evidence of association. The purpose of this study is to examine T2D association of tag SNPs in the <it>TNF</it>/<it>LTA </it>region capturing the majority of common variation in a large-scale sample set of UK/Irish origin.</p> <p>Methods</p> <p>This study comprised a case-control (1520 cases and 2570 control samples) and a family-based component (423 parent-offspring trios). Eleven tag SNPs (rs928815, rs909253, rs746868, rs1041981 (T60N), rs1800750, rs1800629 (G-308A), rs361525 (G-238A), rs3093662, rs3093664, rs3093665, and rs3093668) were selected across the <it>TNF</it>/<it>LTA </it>locus and genotyped using a fluorescence-based competitive allele specific assay. Quality control of the obtained genotypes was performed prior to single- and multi-point association analyses under the additive model.</p> <p>Results</p> <p>We did not find any consistent SNP associations with T2D in the case-control or family-based datasets.</p> <p>Conclusions</p> <p>The present study, designed to analyse a set of tag SNPs specifically selected to capture the majority of common variation in the <it>TNF</it>/<it>LTA </it>gene region, found no robust evidence for association with T2D. To investigate the presence of smaller effects of <it>TNF</it>/<it>LTA </it>gene variation with T2D, a large-scale meta-analysis will be required.</p>