Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) play an important role in reproductive physiology. Both hCG and LH bind to the same lutropin/choriogonadotropin receptor (LH/CG-R). Recent reports documented the temporal and spatial expression of LH/CG-R in the developing and mature mammalian brain. Administration of hCG promoted nerve regeneration in vivo and neurite outgrowth and survival of primary neurons in vitro. The function of hCG/LH and LH/CG-R in the nervous system remains unclear. In this study we report hCG/LH induced distinct morphological and biochemical changes, characteristic of neuronal differentiation, in PC12 cells stably expressing LH/CG-R, and that the differentiation effect is ligand dose- and time-dependent. Western blot analysis revealed that both the extracellular signal-regulated kinases (ERKs) and p38 mitogen-activated protein kinase (MAPK) are activated after hCG treatment. Inhibitor studies revealed both the ERK and p38 MAPK signal transduction pathways are required for this differentiation process which is cAMP-dependent and protein kinase A (PKA)-independent. These findings imply a potential role for hCG/LH and LH/CG-R in the development, maintenance and regeneration of the mammalian nervous system, and a potential in the neuropathogenesis of genetic diseases cause by a mutated LH/CG-R.