Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH-immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH-immunoreactive fibers correlated with the PD stage (r = −0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = −0.61, P < 0.001), and disease duration (r = −0.63, P < 0.001). Immunohistochemistry for α-synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of α-synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and α-synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity. © 2008 Movement Disorder Society.