PurposeThe radiopharmaceutical [18F]AlF-NOTA-FAPI-04 presents a promising alternative to 68 Ga-FAPI owing to its relatively longer half-life. This study aimed to evaluate the clinical usefulness of [18F]AlF-NOTA-FAPI-04 PET/CT for the diagnosis of primary and metastatic lesions in various types of gastrointestinal system cancers, compared with 18F-FDG PET/CT.MethodsPatients diagnosed with gastrointestinal system malignancies were prospectively enrolled. All patients underwent both 18F-FDG and 18F-FAPI-04 PET/CT scans within one week, with 44 (73.3%) for cancer staging and 16 (26.7%) for tumor restaging. Diagnostic efficacy of the primary tumor, as well as the presence and number of lymph nodes and distant metastases, were assessed. Tumor uptake was quantified by the maximum standard uptake value (SUVmax).ResultsFor detection of primary tumor, the diagnostic sensitivity of 18F-FDG PET/CT was 72.7%, while it was 97.7% for 18F-FAPI-04 PET/CT. Based on per-lymph node analysis, the sensitivity, specificity, and accuracy of 18F-FAPI-04 PET/CT in diagnosing metastatic lymph nodes were 91.89%, 92.00%, and 91.96%, respectively. These values were notably higher than those 18F-FDG PET/CT (79.72%, 81.33% and 80.80%, respectively). The 18F-FAPI-04 PET/CT surpassed 18F-FDG PET/CT in detecting suspected metastases in the brain (7 vs. 3), liver (39 vs. 20), bone (79 vs. 51), lung (11 vs. 4), and peritoneal carcinoma (48 vs. 22). Based on per-patient analysis, differential diagnostic accuracies (18F-FAPI-04 vs. 18F-FDG PET/CT) were observed in all patients (91.7% vs. 76.7%), the initial staging group (90.9% vs. 79.5%), and the re-staging group (93.8% vs. 68.7%). Additionally, 18F-FAPI-04 PET/CT revised final diagnosis in 31.7% of patients, contrasting with 18F-FDG PET/CT, and prompted changes in clinical management for 21.7% of the patients.Conclusion18F-FAPI-04 PET/CT outperforms 18F-FDG PET/CT in delineating the primary gastrointestinal tumors and detecting suspected metastatic lesions due to a higher target-to-background ratio (TBR). Moreover, 18F-FAPI-04 PET/CT could provide valuable guidance for tumor staging, thereby having a potential impact on patient management.