Background: Clinical glioblastoma treatment mostly focuses on the contrast-enhancing tumor mass. Amino acid positron emission tomography (PET) can detect additional, nonenhancing glioblastoma-infiltrated brain regions that are difficult to distinguish on conventional magnetic resonance imaging (MRI). We combined MRI with perfusion imaging and amino acid PET to evaluate such nonenhancing glioblastoma regions. Methods: Structural MRI, relative cerebral blood volume (rCBV) maps from perfusion MRI, and alpha-[C-11]-methyl-l-tryptophan (AMT)-PET images were analyzed in 20 patients with glioblastoma. The AMT uptake and rCBV (expressed as tumor to normal [T/N] ratios) were compared in nonenhancing tumor portions showing increased signal on T2/fluid-attenuated inversion recovery (T2/FLAIR) images. Results: Thirteen (65%) tumors showed robust heterogeneity in nonenhancing T2/FLAIR hyperintense areas on AMT-PET, whereas the nonenhancing regions in the remaining 7 cases had homogeneous AMT uptake (low in 6, high in 1). AMT and rCBV T/N ratios showed only a moderate correlation in the nonenhancing regions (r = 0.41, P = .017), but regions with very low rCBV (<0.79 T/N ratio) had invariably low AMT uptake. Conclusions: The findings demonstrate the metabolic and perfusion heterogeneity of nonenhancing T2/FLAIR hyperintense glioblastoma regions. Amino acid PET imaging of such regions can detect glioma-infiltrated brain for treatment targeting; however, very low rCBV values outside the contrast-enhancing tumor mass make increased AMT uptake in nonenhancing glioblastoma regions unlikely.