Differentiating the Parkinson variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD) and other forms of atypical parkinsonism can be difficult because symptoms overlap considerably. 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful imaging technique that can assist in the diagnosis of MSA-P via detection of putaminal and cerebellar hypometabolism. Recent studies suggest that diffusion-weighted imaging (DWI) might be of similar diagnostic value, as it can detect microstructural damage in the putamen by means of an increased mean diffusivity (MD). The aim of this study was a direct comparison of DWI and FDG-PET by using both methods on the same subject cohort. To this end, combined DWI and FDG-PET were employed in patients with MSA-P (n = 11), PD (n = 13), progressive supranuclear palsy (n = 8), and in 6 control subjects. MD values and FDG uptake ratios were derived from volumetric parcellations of the putamen and subjected to further analysis of covariance (ANCOVA) and receiver operating characteristics analyses. MSA-P was found to be associated with an increased posterior putaminal MD (P < 0.001 in all subgroup comparisons) that correlated strongly with local reductions in FDG uptake (r = -0.85, P = 0.002). DWI discriminated patients with MSA-P from other subgroups nearly as accurately as FDG-PET (area under the curve = 0.89 vs 0.95, P = 0.27 [pooled data]). Our data suggest a close association between the amount of putaminal microstructural damage and a reduced energy metabolism in patients with MSA-P. The clinical use of DWI for the differential diagnosis of MSA-P is encouraged.