L-Carnitine (LC) is a nutrient with an essential role in cellular energy production. At high doses, LC can mimic some of the biological activities of glucocorticoids, particularly immunomodulation. To explore the molecular bases of this property, we tested the influence of LC on glucocorticoid receptor-a (GRalpha) functions. LC reduced the binding capacity of GRalpha, induced its nuclear translocation, and stimulated its transcriptional activity. Moreover, LC suppressed TNFalpha and IL-12 release from human monocytes in glucocorticoid-like fashion. We conclude that pharmacologic doses of LC can activate GRalpha and, via this mechanism, regulate glucocorticoid-responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids.