Background: As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), F-18-9-fluoropropyldihydrotetrabenazine (F-18-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP). Objective: We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using F-18-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP. Methods: We recruited 58 patients with PSP, 23 age- and duration-matched patients with PD, as well as 17 HCs. Patients were scanned using F-18-FP-DTBZ PET/computed tomography, and images were spatially normalized and analyzed based on the volume of interest. Results: VMAT2 binding differed significantly in the striatum and substantia nigra among the groups (P < 0.001). A more severe disruption in the caudate was noted in the PSP group (P < 0.001) than in the PD group. However, no differences were found in the nucleus accumbens, hippocampus, amygdala, or raphe between the PD and PSP groups. Within the PSP group, striatal VMAT2 binding was significantly associated with the fall/postural stability subscore of the PSP Rating Scale, especially in the putamen. Furthermore, VMAT2 binding was correlated with Mini-Mental State Examination or Montreal Cognitive Assessment in the hippocampus. Conclusions: Caudate disruptions showed prominent differences among the groups. VAMT2 binding in the striatum and hippocampus reflects the severity of fall/postural stability and cognition, respectively. (c) 2024 International Parkinson and Movement Disorder Society. (c) 2024 International Parkinson and Movement Disorder Society.