Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson's disease (PD). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1 alpha is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1 alpha and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1 alpha by FGF21 occurred via the NAD(+)-dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1 alpha and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD.