Fas-associated factor 1 or FAF1 is a Fas-binding protein implicated in apoptosis. FAF1 is the product of a gene at PARK 10 locus on chromosome 1p32, a locus associated with late-onset PD [Hicks, A.A., Petursson, H., Jonsson, T., Stefansson, H., Johannsdottir, H.S., Sainz, J., Frigge, M.L.et al., 2002. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol. 52, 549-555.]. In the present study we investigated the role of FAF1 in cell death and in Parkinson's disease (PD) pathogenesis. FAF1 levels were significantly increased in frontal cortex of PD as well as in PD cases with Alzheimer's disease (AD) pathology compared to control cases. Changes in FAF1 expression were specific to PD-related alpha-synuclein pathology and nigral cell loss. In addition, PD-related insults including, mitochondrial complex I inhibition, oxidative stress, and increased alpha-synuclein expression specifically increased endogenous FAF1 expression in vitro. Increased FAF1 levels induced cell death and significantly potentiated toxic effects of PD-related stressors including, oxidative stress, mitochondrial complex I inhibition and proteasomal inhibition. These studies, together with previous genetic linkage studies, highlight the potential significance of FAF1 in pathogenesis of idiopathic PD.