Increased activity of the subthalamic nucleus (STN) is critical in mediating motor symptoms of Parkinson's disease. To determine if altered STN activity also occurs in levodopa (L-Dopa)-unresponsive parkinsonism due to a combined nigral and striatal degeneration, metabolic activity of the STN was assessed using cytochrome oxidase (CO) histochemistry in monkeys with nigral, striatal, or nigral+striatal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and/or 3-nitropropionic acid (3NP). MPTP- and MPTP+3NP-treated monkeys had a similar parkinsonian score and were clinically indistinguishable. However, CO activity in the STN was significantly increased in MPTP-induced parkinsonism but not in MPTP+3NP-induced striatonigral degeneration. These results indicate that metabolic activity of the STN is normal following a combined nigral+striatal degeneration and may help to understand the lack of effect of STN stimulation in L-Dopa-unresponsive parkinsonism.