Background <p>Despite the clinical utility of [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) in evaluating patients with unresponsive wakefulness syndrome (UWS), its use is constrained by high cost, limited availability, the need for radioactive tracers, and other factors. Arterial spin labeling (ASL) provides a noninvasive measure of cerebral perfusion, yet direct comparisons with FDG-PET in the same cohort of patients with UWS appear to be lacking. We therefore aimed to assess the feasibility and potential clinical relevance of ASL relative to FDG-PET in this cohort.</p> Methods <p>This prospective observational study included 33 participants with UWS (10 female; mean age, 49.48 ± 14.9&#xa0;years) and 17 healthy controls (HCs) (9 female; mean age, 31.9 ± 9.6&#xa0;years). Participants underwent FDG-PET and ASL scans to measure metabolism (via glucose uptake) and cerebral blood flow (CBF), respectively. CBF and metabolism in the UWS and HC cohorts were compared, globally and for seven functional networks. Comparability of the two modalities was estimated using partial correlation for both global and network levels. Crossmodal validation was further performed by testing the generalizability of machine learning classifiers trained on ASL data to positron emission tomography (PET) data and, conversely, classifiers trained on PET data to ASL data.</p> Results <p>ASL revealed decreased CBF in patients with UWS relative to HCs, consistent with reductions in glucose metabolism observed for FDG-PET. Positive correlations were observed between CBF and metabolism across the global brain and most networks. Crossmodal validation demonstrated correspondence and complementary discriminatory information between ASL and PET data.</p> Conclusions <p>Our results provide proof-of-concept evidence that ASL is comparable to and complementary with FDG-PET; together with the practical advantages of ASL, these findings support further investigation of ASL in the clinical assessment of UWS.</p>