Abstract Background and Hypothesis Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood–brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD. Study Design We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions. Study Results Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions. Conclusions This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia.