Parkinson’s disease (PD) is increasingly recognized as a heterogeneous disorder, with rapid eye movement sleep behavior disorder (RBD) serving as a key prodromal marker for a distinct, aggressive subtype. This study investigates the plasma neuron-derived extracellular vesicle (EV) proteome to delineate molecular differences between PD patients with RBD (PD-RBD) and those without (PD-noRBD). Using L1CAM-based immunoprecipitation and Data-independent acquisition mass spectrometry (DIA-MS) proteomics, we identified 1,354 proteins across 28 subjects. Comparative analysis revealed 239 differentially expressed proteins (DEPs) between PD-RBD and PD-noRBD. Functional enrichment and PPI network analyses uncovered divergent pathobiological signatures: PD-noRBD was dominated by dysregulated lipid metabolism (APOE, CETP, PLTP) and systemic inflammation, while PD-RBD exhibited pronounced extracellular matrix remodeling (COL3A1, MMP7, VCAN) and complement activation. Correlations with clinical features and brain iron deposition (via quantitative susceptibility mapping, QSM) further linked specific DEPs to motor severity, disease duration, and autonomic symptoms. Notably, α-synuclein (SNCA) levels were significantly higher in PD-RBD. A series of biomarker candidates in differentiating subtypes were identified. These findings provide compelling evidence that PD-RBD and PD-noRBD represent distinct molecular entities, driven by divergent pathogenic mechanisms involving metabolic-inflammation versus structural-extracellular matrix (ECM) pathways. This proteomic map offers a valuable resource for developing subtype-specific diagnostic tools and targeted therapeutic strategies, advancing the field toward precision medicine for Parkinson’s disease.