Manganese chloride increased cell mortality when added to human fibroblast cultures. The toxicity of the metal was greatly enhanced by dopamine; this effect was antagonized by the presence in the culture medium of catalase and superoxide dismutase enzymes. Manganese chloride also caused a marked decrease of striatal dopamine concentrations when infused into rat substantia nigra. Manganese neurotoxicity was lowered by pretreating the animals with drugs that reduced striatal dopamine turnover rate. Administration of an antioxidant, such as vitamin E, also partially prevented striatal dopamine decline induced by intranigral manganese infusion. Therefore, the decreased availability or autoxidation of dopamine attenuated manganese neurotoxicity. These findings are in agreement with previous observations suggesting that manganese increases toxic products originating from dopamine catabolism.