Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) associated to the aggregation of α-synuclein (α-Syn) that forms intraneuronal inclusions. In addition, mounting evidence suggest that neuro-immune interactions, favoured by cerebrovascular alterations, are involved in the pathomechanisms of PD. In this work, we focus on a myeloid population that surrounds blood vessels: perivascular macrophages (PVMs). We show that both in PD patients and in a mouse model of degenerative synucleinopathy, there is an increased proliferative recruitment of PVMs within the SN. We also found that specific ablation of PVMs aggravates the degenerative phenotype in synucleinopathic mice. PVMs-mediated neuroprotection is not likely linked to regulatory mechanisms of microglial cell response. Interestingly, the absence of PVMs is associated with higher vascular expression of VCAM-1 and enhanced infiltration of CD4+ and CD8+ T-cells, whose pathogenic role remains to be determined. We also observe that PVMs deficiency leads to an increased spreading of α-Syn pathology following striatal injections of α-Syn fibrils. We hypothesize that PVMs might be essential for the clearance of toxic α-Syn species due to their phagocytic activity, but also to their importance in regulating interstitial and cerebrospinal fluid (CSF) circulation, as shown by analysing CSF movement via the infusion of fluorescent tracers in PVMs-deficient conditions. Overall, our data highlight the importance of PVMs in regulating the toxicity and propagation of synucleinopathy and provide a rationale for therapeutic strategies aimed at boosting PVMs functions in PD.