The positron emission tomography (PET) radioligand for adenosine A receptor (A1R) [1-methyl-C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX) has recently been developed for human brain imaging. In the present study, we evaluated the alteration of the A1R in patients with diffuse axonal injury (DAI) in chronic stage in vivo. Ten patients with DAI (7 men and 3 women) were included in this study. Three PET examinations were sequentially performed to measure A1R binding with C-MPDX, glucose metabolism withF-fluorodeoxyglucose (FDG), and central benzodiazepine receptor binding with C-flumazenil (FMZ), and decreases ofC-FMZ uptake indicate neuronal loss. C- MPDX did not depict any lesion with significantly decreased nondisplaceable binding potential (BP) in comparison to healthy controls (14 men) in region of interest (ROI) analysis. Instead, it showed a significant increase of BP in the lower frontal and posterior cingulate cortexes and rolandic area (p < 0.05) in ROI analysis. In F-FDG PET, the standardized uptake values (SUVs) ratio to the whole brain were decreased in anterior and posterior cingulate gyrus compared to controls (14 men and 9 women; p< 0.01). In C-FMZ PET, the SUV ratio to the cerebellum was decreased in anterior cingulate gyrus in ROI analysis (controls, 9 men and 6 women; p< 0.01). The area with significantly increased C-MPDX binding, lower frontal cortex, rolandic area, and posterior cingulate gyrus, did not overlap with the areas of neuronal loss detected by decreasedC-FMZ binding and did not completely overlap with area of reducedF-FDG uptake. We obtained the first C-MPDX PET images reflecting the A1R BP in human DAI brain in vivo. C-MPDX depicted increased A1R BP in the areas surrounding the injured brain, whereas F-FDG demonstrated reduction throughout the brain. The results suggested that A1R might continuously confer neuroprotective or neuromodulatory effects in DAI even in the chronic stage.