The substantia nigra plays important roles in the brain function and is critical in the development of many diseases, particularly Parkinson's disease. Pathological changes of the substantia nigra have also been reported in other neurodegenerative diseases. Using a quantitative proteomic approach, we investigated protein expressions in the substantia nigra of Alzheimer's disease, Huntington's disease, and Multiple sclerosis. The expression level of one hundred and four proteins that were identified in at least three samples of each group were compared with the control group, with nineteen, twenty-two and thirteen proteins differentially expressed in Alzheimer's diseases, Huntington's disease and Multiple sclerosis respectively. The result indicates that the substantia nigra also undergoes functional adaption or damage in these diseases.