Obesity is associated with impaired fatty acid (FA) oxidation and increased de novo hepatic lipogenesis that may contribute to the development of hypertriglyceridemia, an important risk factor for the development of cardiovascular disease. Strategies to improve hepatocyte FA metabolism, including dietary interventions, are therefore important for the prevention of obesity-associated co-morbidities. Farnesol is consumed in the diet as a component of plant products. In the present study, we administered farnesol orally to rats for seven days and found significantly reduced serum triglyceride concentrations compared with controls. Potential mechanisms underlying the hypotriglyceridemic effect of farnesol were investigated using clone-9 cultured rat hepatocytes. Farnesol significantly upregulated expression of peroxisome proliferator-activated receptor alpha (PPARalpha) and the PPARalpha-regulated genes fatty acyl-CoA oxidase and carnitine palmitoyl transferase 1a, suggesting that increased hepatic FA oxidation may contribute to serum triglyceride lowering in rats. Farnesol did not change SREBP-1c mRNA levels, but significantly down-regulated fatty acid synthase (FAS) mRNA and protein levels and activity, indicating that attenuated lipogenesis may also contribute to hypotriglyceridemic effects of farnesol in vivo. Rescue experiments revealed that down-regulation of FAS by farnesol was not related to activation of PPARalpha, but rather was caused by a 9-cis retinoic acid mediated mechanism that involved down-regulation of retinoid X receptor beta. Diets rich in plant products are associated with a lower risk of cardiovascular disease. Our findings suggest that farnesol may contribute to this protective effect by lowering serum TG levels.