Abstract: The mechanism of cytotoxicity of l-DOPA was studied in the rat pheochromocytoma PC12 cell line. The cytotoxicity of l-DOPA to PC12 cells was time and concentration dependent. Carbidopa, which inhibited the conversion of l-DOPA to dopamine, did not protect against l-DOPA cytotoxicity in PC12 cells. Furthermore, clorgyline, a selective inhibitor of monoamine oxidase type A, and pargyline, an inhibitor of both monoamine oxidase types A and B, both did not have an effect on l-DOPA toxicity. These findings suggest that cytotoxicity was not due to dopamine formed from l-DOPA. Catalase or superoxide dismutase each partially protected against l-DOPA toxicity in PC12 cells. In combination, the effects were synergistic and provided almost total protection against cytotoxicity. 6-Cyano-7-nitroquinoxaline-2,3-dione, an antagonist of non-NMDA receptors, did not protect against l-DOPA toxicity. These data suggest that toxicity of l-DOPA is most likely due to the action of free radicals formed as a result of its autoxidation. Furthermore, these findings suggest that patients on long-term l-DOPA therapy are potentially at risk from the toxic intermediates formed as a result of its autoxidation.