Technical Abstract: Pterostilbene, a stilbenoid antioxidant found in blueberries, grapes, other small fruits, and in woody plants was shown to activate the peroxisome proliferator-activated receptor alpha (PPAR alpha) isoform. This nuclear receptor is proposed to mediate the activity of lipid-lowering drugs such as the fibrates. Pterostilbene was evaluated together with resveratrol, piceatannol and resveratrol trimethylether along with ciprofibrate (positive control), for the activation of endogenous PPAR alpha in H4IIEC3 cells transfected with a peroxisome proliferator response element-AB (rat fatty acyl CoA beta-oxidase response element) - luciferase gene reporter construct. Pterostilbene demonstrated the highest induction of PPAR alpha showing 8- and 14-fold increases in luciferase activity at 100 and 300 µM, respectively, relative to the control. The maximal luciferase activity responses to pterostilbene were higher than those obtained with the hypolipidemic drug, ciprofibrate (33910 and 19460 relative luciferase units, respectively), at 100 µM. Hypercholesterolemic hamsters fed with pterostilbene at 25 ppm of the diet showed 29% lower plasma low-density lipoprotein cholesterol, 7% higher plasma high-density lipoprotein cholesterol, and 14% lower plasma glucose compared to the control group. The LDL/HDL ratio was also statistically significantly lower for pterostilbene, as compared to results for the control animals, at this diet concentration. These results are similar to those obtained in a published study with fenofibrate, a known PPAR alpha specific agonist, in hamsters fed high fat diets. Taken collectively, the data on lipid- and glucose-lowering effects suggest that pterostilbene acts as a PPAR alpha agonist and possesses lipid- and glucose-lowering effects in vivo, like that of the fibrate class, and appears to be a more effective PPAR alpha agonist and hypolipidemic agent than resveratrol, a constituent in grapes and wine reported to have hypolipidemic properties.