The immunohistochemical localization of Met-enkephalin (Enk) was examined in the brains of normal monkeys (Macaca nemistrina), monkeys made parkinsonian by systemic MPTP administration and sacrificed while symptomatic, and monkeys exposed to low doses of MPTP over several months and sacrificed while asymptomatic for a gross parkinsonian motor disorder. The animals that had severe parkinsonian features had a large number of intensely Enk-immunoreactive perikarya in the putamen. Normal control animals had no Enk-immunoreactive perikarya while asymptomatic animals had small numbers of lightly to moderately stained perikarya in the putamen. Symptomatic animals also showed the most intense Enk immunoreactivity in the lateral globus pallidus (LGP) while the asymptomatic animals showed LGP Enk immunoreactivity intermediate between that seen in symptomatic and normal animals. These results suggest an increase in putamen Enk synthesis and LGP Enk content in animals with massive striatal dopamine depletions (greater than or equal to 97%) and which actively show parkinsonian features. Animals with slightly less striatal dopamine depletion and with no parkinsonian symptoms, had increased activity in this system but not to the extent seen in symptomatic animals.