Insulin resistance, which is pathogenic for type 2 diabetes (T2D), is under the control of largely unknown genetic determinants. LAR, a protein-tyrosine phosphatase which inhibits insulin signalling, is overexpressed in animal and human models of insulin resistance. We studied the entire sequence of the LAR gene by SSCP analysis and automatic DNA sequencing, with the aim of verifying whether its sequence variants might be associated with insulin resistance. In the 276 bp sequence upstream of the transcriptional start site (i.e. a region we have identified as having basal promoter activity) a -127 bp T-->A SNP (5% frequency) was associated with lower body mass index (BMI) ( P=0.03), waist circumference ( P=0.01), blood pressure ( P=0.01) and urinary albumin/creatinine ratio ( P=0.04) in 589 non-diabetic unrelated individuals from the Gargano region (central east coast of Italy). To quantify the risk for a high body weight conferred by the -127 T-->A SNP, the whole cohort was divided into tertiles according to the individual BMI. The risk of belonging to the heavier tertile, as compared to the leaner one, was reduced by approximately 60%. In a population from East Sicily ( n=307), T/A genotype carriers ( n=13) showed lower triglyceride levels ( P=0.04) and higher insulin sensitivity as indicated by lower plasma glucose ( P=0.03) and serum insulin ( P=0.006) during oral glucose tolerance testing (OGTT). Promoter activity, studied by cDNA transfection experiments, was similar for the A and T alleles. In conclusion, a genetic variant of the LAR gene promoter is consistently associated with features of insulin resistance in two different Caucasian populations. Although the biological relevance of this variant has yet to be determined, this finding underlines the potential importance of the LAR gene in dysregulation of insulin sensitivity and related disorders.