BACKGROUND: Crohn disease is a chronic granulomatous inflammatory disease of gastrointestinal tract. Previous studies showed Crohn disease strictures overexpress fibroblast activation protein and had active 68 Ga-FAPI-04 uptake. Our study was to compare the diagnostic performance of 68 Ga-FAPI-04 and 18 F-FDG PET/CT in Crohn disease. PATIENTS AND METHODS: This is a prospective cohort study recruiting patients with newly diagnosed or relapsed Crohn disease. All the patients underwent 68 Ga-FAPI-04 and 18 F-FDG PET/CT. The diagnostic performance of the 2 PET/CT modalities and their uptake values were compared. The correlation of PET semiquantitative parameters [metabolic intestinal volume (MIV FDG and MIV FAPI ), total intestinal uptake (TIU FDG and TIU FAPI )] with clinical biomarkers were also analyzed. RESULTS: Seventeen participants (13 men and 4 women, age 32.3 +/- 15.9 y) were recruited. The sensitivity of 68 Ga-FAPI-04 and 18 F-FDG PET/CT in detecting Crohn lesions were 90.0% and 85.0%, and the specificities were 93.0% and 88.4%, respectively. In receiver operating characteristic curve analysis, 68 Ga-FAPI-04 PET/CT [area under the curve = 0.92 (95% CI: 0.83-0.97), P < 0.001] showed better diagnostic performance compared with 18 F-FDG PET/CT [area under the curve = 0.87 (95% CI: 0.78-0.93), P < 0.001; P = 0.043]. The SUVmax of 68 Ga-FAPI and 18 F-FDG in stricture/fistula lesions were significantly higher than those in non-stricture/fistula lesions ( 68 Ga-FAPI, 10.9 +/- 6.7 vs 5.0 +/- 3.5, P = 0.0002; 18 F-FDG, 9.5 +/- 4.9 vs 5.3 +/- 1.8, P = 0.0016). TIU FAPI and MIV FAPI of 68 Ga-FAPI-04 PET/CT were significantly correlated with high sensitivity C-reactive protein and simple endoscopic score for Crohn disease ( P < 0.05). TIU FDG and MIV FDG of 18 F-FDG PET/CT were also correlated with simple endoscopic scores for Crohn disease ( P < 0.05). CONCLUSIONS: 68 Ga-FAPI-04 PET/CT showed better diagnostic performance than 18 F-FDG PET/CT in Crohn disease.