To test the hypothesis that free fatty acids (FFAs) modulate microvascular function and that this contributes to obesity-associated insulin resistance, hypertension, and microangiopathy, we examined the effects of both FFA elevation in lean women and FFA lowering in obese women on skin microvascular function. A total of 16 lean and 12 obese women underwent, respectively, Intralipid plus heparin (or saline) infusion and overnight acipimox (or placebo) treatment. We measured capillary recruitment with capillaroscopy and endothelium-(in)dependent vasodilation by iontophoresis of acetylcholine and sodium nitroprusside before and during hyperinsulinemia (40 mU . m(-2) . min(-1)). FFA elevation impaired capillary recruitment and acetylcholine-mediated vasodilation before (44.6 +/- 16.8 vs. 56.9 +/- 18.9%, P < 0.05; and 338 +/- 131 vs. 557 +/- 162%, P < 0.01, respectively) and during (54.0 +/- 21.3 vs. 72.4 +/- 25.4%, P < 0.01; and 264 +/- 186 vs. 685 +/- 199%, P < 0.01, respectively) hyperinsulinemia. FFA lowering improved capillary recruitment before (50.9 +/- 14.6 vs. 37.4 +/- 9.3%, P < 0.01) and during (66.8 +/- 20.6 vs. 54.8 +/- 15.4%, P < 0.05) hyperinsulinemia. Changes in FFA levels were inversely associated with changes in capillary recruitment and insulin sensitivity in lean (r = -0.46, P = 0.08; and r = -0.56, P = 0.03) and in obese (r = -0.70, P = 0.02; and r = -0.62, P = 0.04) women. Regression analyses showed that changes in capillary recruitment statistically explained approximately 29% of the association between changes in FFA levels and insulin sensitivity. In conclusion, FFA levels modulate microvascular function and may contribute to obesity-associated insulin resistance, hypertension, and microangiopathy.