BACKGROUND: The noninvasive evaluation of nigrostriatal dopaminergic integrity by PET can provide useful information for the differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). OBJECTIVES: To evaluate the diagnostic potential of imaging striatal monoaminergic terminal integrity with the novel vesicular monoamine transporter type 2 (VMAT2) radioligand [(18)F]AV-133 and PET to distinguish DLB from AD. METHODS: Fifty participants [9 DLB, 11 AD, 20 Parkinson's disease (PD) and 10 healthy age-matched control subjects (HC)] underwent [(18)F]AV-133 PET studies. Additionally, 20 participants underwent amyloid imaging PET scans with either [(11)C]PiB or (18)F-florbetaben. VMAT2 density was calculated through normalized tissue uptake value ratios (R(T)) at 120-140 min after injection using the primary visual or the cerebellar cortex as reference region. Comparison of the R(T) for [(18)F]AV-133 was done between the different clinical diagnostic groups. RESULTS: Significantly lower striatal VMAT2 densities were observed in DLB and PD when compared to AD and HC, especially in the posterior putamen. In contrast to PD and DLB, no reductions were observed in AD patients when compared to HC. CONCLUSIONS: [(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. In contrast to amyloid imaging, VMAT2 imaging with [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in DLB patients, assisting in the differential diagnosis from AD.