Parkinson's disease (PD) results from the selective loss of dopaminergic neurons from the substantia nigra compacta (SNc). Whilst the cause of dopamine cell loss in Parkinson’s disease (PD) is unknown, it is clear that the male-sex is a strong risk factor. The incidence and prevalence of PD is 2-fold higher and disease progression more rapid in males than females. Growing evidence suggests that sex-specific genes contribute to this male-bias in PD. We previously showed that the male-sex determining gene encoded by the Y chromosome and therefore only found in males, SRY, co-localises with male dopamine neurons, where it regulates dopamine biosynthesis and motor function.Here, we investigated the regulation and function of nigral SRY in normal and 6-hydroxydopamine (6-OHDA) or rotenone lesioned hemiparkinsonian rats. Results show that SRY has a detrimental effect in males in animal models of Parkinson’s disease. Specifically, we found that mid-brain SRY levels are aberrantly upregulated. Infusing antisense SRY DNA to downregulate SRY levels in the mid-brain led to a reduced in movement deficits and brain cell death. We also observed marked reductions in DNA damage, mitochondrial degradation and neuroinflammation in the mid-brain. These results suggest contribution to male sex bias in Parkinson’s disease with implications for ADHD, autism and schizophrenia.