Daily stress is associated with increased risk for various diseases, and numerous studies have provided evidence that environmental stress leads to deleterious effects on the central nervous system. However, it remains unclear whether chronic stress exacerbates the progression of Parkinson's disease (PD). To investigate this hypothesis, we determined the effect of chronic mild stress (CMS) on the pathogenesis of PD in a transgenic mice line that overexpresses the human A53T mutant α-synuclein (A53T Tg mice). We show that when exposed to CMS, male, but not female, A53T Tg mice developed profound motor disabilities and exhibited olfactory sensitivity deficits. Pathological analysis also identified robust dopaminergic neuron degeneration and strong reduction of dopamine levels in A53T Tg male mice who underwent CMS treatment. Systematic examination of the abnormal aggregation of α-synuclein revealed a profound increase of inclusion in A53T Tg male mice subject to CMS resembling key pathological changes of PD. An insight into the mechanism underlying stress leading to the acceleration of neurodegeneration in those with genetic susceptibility, was revealed by evidence of microglia activation and elevated pro-inflammatory factor levels in A53T Tg male mice following CMS. Notably, these effects of CMS on the pathogenesis of PD showed a remarkable sexual dimorphism: only male A53T Tg mice exhibited exacerbation of the progression of PD. However, the molecular and cellular bases for this difference remains to be elucidated. Our results indicate a causative role for chronic mild stress using a PD animal model. Based on these findings, we propose that CMS acts as an environmental risk factor that leads to neuroinflammation and progressive neurodegeneration on a background of PD susceptibility.