Abstract: We have recently shown that elevated levels of free fatty acid (FFA) seen in insulin‐resistant obese subjects are associated with endothelial dysfunction. l‐Carnitine, which is required for mitochondrial FFA transport/oxidation, has been reported to improve vascular function in subjects with diabetes and heart disease. Here, we tested the hypothesis that l‐carnitine attenuates FFA‐induced endothelial dysfunction. We studied leg blood flow (LBF) responses and leg vascular resistance (LVR) to graded intrafemoral artery infusions of the endothelium‐dependent vasodilator, methacholine chloride (MCh). A group (n= 7) of normal lean subjects was studied under basal conditions (saline), after 2 h of FFA elevation (FFA), and then after 2 h of superimposing l‐carnitine on FFA elevation. FFA elevation caused the maximal LBF increment in response to MCh to decrease from 0.388 ± 0.08 to 0.212 ± 0.071 L/min (P= 0.05). Similarly, FFA blunted the maximum decrease in LVR in response to MCh from −315 ± 41 U to −105 ± 46 U (P= 0.05). The superimposed l‐carnitine restored the LBF increment in response to MCh to 0.488 ± 0.088 L/min (P= 0.05 vs. FFA) and the maximum fall in LVR to −287 ± 75 U (P= 0.05 vs. FFA), indicating that l‐carnitine elevation may attenuate FFA‐induced endothelial dysfunction. In conclusion, our data suggest that increasing l‐carnitine levels may improve FFA‐induced and obesity‐associated endothelial dysfunction. This improved endothelial function may delay or prevent the development of excess cardiovascular disease.