The ability of pigment epithelium-derived factor (PEDF) to promote neurite outgrowth of retinal cells through mitogen-activated protein kinase (MAPK) pathways was examined. Neurite outgrowth effects of PEDF were determined by quantifying the neurite length extending from cultured chick embryo retinal explants, and neurite outgrowth ratio of R28 cells (a neural cell line derived from the neonatal rat retina). MAPK activity levels were determined by inhibition assays. The contribution of signaling pathway was quantified with a specific inhibitor for MAPK: PD98059. PEDF (50 ng/ml) promoted chick retinal neurite elongation and increased the extent of R28 cell neurite outgrowth. PD98059 decreased neurite elongation of chicken retinal explants and the extent of R28 cell neurite outgrowth. PEDF possibly promotes neurite outgrowth for retinal cells by activating MAPK pathways. These data suggest that PEDF provides a useful support for retinal cells through the MAPK pathway and leads to the progress of therapy for many retinal diseases.