Background <p>Several lines of evidence support the hypothesis of brain-first and body-first Parkinson’s disease (PD) subtypes, characterized by distinct origins of α-synuclein pathology. However, data on premotor non-motor burden and motor progression in these subtypes remain inconsistent.</p> Objective <p>To analyze the natural history of body-first versus brain-first PD subtypes.</p> Methods <p>Data from 400 PD patients enrolled at a single Italian center were analyzed. All patients underwent a standardized retrospective baseline assessment of premotor and motor symptoms at onset and were prospectively followed. Premotor REM sleep behavior disorder (RBD), considered a prodromal phenotype of the body-first subtype, was used to divide patients into two groups: 81 patients with probable premotor RBD (PD^preRBD+) and 319 patients without (PD^preRBD−).</p> Results <p>At motor onset, PD^preRBD+ patients were older than PD^preRBD− patients, exhibited less tremor, and more frequently presented with bilateral motor symptoms. PD^preRBD+ patients also reported a greater burden of premotor symptoms, including hyposmia, cognitive impairment, pain, constipation, and other dysautonomic symptoms. Over the follow-up period, PD^preRBD+ patients progressed more rapidly to Hoehn and Yahr stage 3, even after adjusting for sex, years of schooling, age at motor onset, and initial motor phenotype.</p> Conclusions <p>Our results align with the hypothesis of brain-first and body-first PD subtypes, providing novel insights into their different premotor non-motor burden and motor progression trajectories.</p>