Neurotoxicity induced by 6-hydroxydopamine (6-OHDA) is believed to be due, in part, to the production of reactive oxygen species (ROS). Antioxidants protect neurons against 6-OHDA-induced neurotoxicity by inhibiting free radical generation. In this study, we investigated whether or not caffeic acid phenethyl ester (CAPE) could protect neurons against 6-OHDA-induced neurotoxicity in cultured rat rostral mesencephalic neurons (RMN) and cerebellar granule neurons (CGN). We now report that exposure of RMN and CGN to 6-OHDA (40 μM for RMN and 70 μM for CGN) resulted in significant increases in free radical production and death of both neuron types. Pretreatment with CAPE (10 μM) for 2 h prevented both 6-OHDA-induced free radical generation and neurotoxicity. Furthermore, CAPE also attenuated H2O2-induced neurotoxicity. Our results strongly suggest that CAPE blocks 6-OHDA-induced neuronal death possibly by inhibiting 6-OHDA-induced free radical generation and blocking free radical-induced neurotoxicity in neurons. Both the antioxidative and neuroprotective effects of CAPE may be beneficial in the therapy for Parkinson's disease and other neurodegenerative diseases.