Identifying DNA mismatch repair deficiency (MMRd) is important for prognosis risk stratification in patients with early-stage endometrial cancer (EC), but there is a notable absence of cost-effective and non-invasive preoperative assessment techniques. The study explored the co-reactivity pattern of glucose metabolism and blood perfusion in EC based on hybrid [18F]fluorodeoxyglucose ([18F]FDG) PET/dynamic contrast enhanced (DCE)-MRI to provide an imaging biomarker for identifying MMRd.Patients with a history of postmenopausal bleeding and initially diagnosed with EC on ultrasound were recruited to perform a PET/DCE-MRI scan. Glucose metabolism parameters were calculated on PET, and blood perfusion parameters were calculated semi-automatically by the DCE-Tofts pharmacokinetic model. The MMRd of early-stage EC was evaluated by immunohistochemistry. The synchronous variation of PET and DCE-MRI parameters was compared between the MMRd and mismatch repair proficiency (MMRp). The association between PET/DCE-MRI and MMRd was analyzed by logistic regression to establish the digital biomarker for predicting MMRd. Receiver operating characteristic curve, decision curve analysis, and the net reclassification index (NRI) were used to evaluate the value of the digital biomarker in identifying MMRd.Eighty-six early-stage EC cases (58.92 ± 10.13 years old, 34 MMRd) were enrolled. The max/mean standardized uptake value (SUVmax/SUVmean), metabolic tumor volume, total lesion glycolysis, transfer constant (Ktrans), and efflux rate (Kep) were higher in MMRd than those in MMRp (P < 0.001, < 0.001, 0.002, 0.004, < 0.001, and 0.005, respectively). The correlations between glucose metabolism and blood perfusion were different between the MMRd and MMRp subgroups. SUVmax was correlated with Kep (r = 0.36) in the MMRd. SUVmean (odds ratio [OR] = 1.32, P = 0.006) and Ktrans (OR = 1.90, P = 0.021) were independent risk factors for MMRd. And the digital biomarker that combined SUVmean and Ktrans outperformed in identifying MMRd in early-stage EC more than DCE-MRI (AUC: 0.83 vs. 0.78, NRI = 13%).A potential digital biomarker based on [18F]FDG PET/DCE-MRI can identify MMRd for prognosis risk stratification in early-stage EC.© 2024. The Author(s).