A polymorphism (C825T) in the gene encoding the G protein beta3 subunit (GNB3) has recently been associated with hypertension and obesity in several populations. The aim of the study was to analyse the relationship between this polymorphism and insulin sensitivity, an hypothesised unifying factor for hypertension and obesity. One hundred thirty unrelated patients with essential hypertension, 70 female and 60 male, aged 58 +/- 1 years with systolic blood pressure of 173 +/- 2 mm Hg and diastolic blood pressure of 105 +/- 1 mm Hg, were genotyped for the GNB3 polymorphism by PCR and restriction digestion with BseDI, and classified in two groups according to the genotypes CC and CT + TT. Body mass index (BMI) was significantly higher in patients with the T allele as compared with patients without the T allele (29.3 +/- 0.4 vs. 26.7 +/- 0.6 kg/m2, p<0.001). On the contrary, there were no differences in the level of systolic or diastolic blood pressure among the genotypes. Insulin sensitivity was measured in a subgroup of 35 patients by means of an euglycemic hyperinsulinemic clamp test. In this subgroup, patients with the T allele displayed lower insulin sensitivity index (1.6 +/- 0.3 vs. 2.7 +/- 0.3 mg/kg/min, p = 0.022), higher fasting serum insulin (121 +/- 16 vs. 77 +/- 11 pmol/L, p = 0.032), higher serum glucose 120 min after 75 g load (9.8 +/- 1.2 vs. 7.0 +/- 0.5 mmol/L, p = 0.038), and higher glycosilated haemoglobin (5.7 +/- 0.4 vs. 4.7 +/- 0.2%; p = 0.042) as compared with patients without the T allele. A regression analysis showed that the association between the T allele and insulin sensitivity was independent of BMI (beta coefficient -0.386, p = 0.022). These results suggest a relationship between the 825T allele of GNB3 and insulin resistance in the essential hypertensive patients studied, which seems to be independent of BMI.