High levels of TSH are associated with an increased cardiovascular risk. Many cardiovascular risk factors cluster within the insulin resistance syndrome. It is not known whether levels of TSH cluster as well. We conducted this research to test the hypothesis that TSH, insulin sensitivity, and levels of low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) are interdependent in euthyroid subjects. Levels of TSH, free thyroid hormone, and serum lipids were measured in fasting serum samples taken before performance of a hyperinsulinemic euglycemic clamp to assess insulin sensitivity in 46 healthy euthyroid subjects with a mean TSH of 1.8 +/- 0.7 mU/L. Significant age- and sex-adjusted partial correlations of TSH with LDL-C (r = 0.48; P < 0.01) and HDL-C (r = -0.36; P < 0.05) were observed. TSH was not significantly correlated with insulin sensitivity or fasting triglyceride concentrations. In line with these results, we found the associations of TSH with LDL-C and HDL-C to be independent of insulin sensitivity. However, we observed significant effect-modification of the association of TSH with LDL-C by insulin sensitivity (P = 0.02). This effect-modification implies a range of associations of TSH with LDL-C that varies from absent in insulin-sensitive subjects to strongly positive in insulin-resistant subjects. We conclude that the increased cardiovascular risk associated with subclinical hypothyroidism seems to extend itself into the normal range of thyroid function. Importantly, the effect-modification of the association of TSH with LDL-C by insulin sensitivity suggests that insulin-resistant subjects are most susceptible to this increased risk.