OBJECTIVE: The purpose of this study is to evaluate the value of contrast-enhanced ultrasound (CEUS) in differential diagnosis of Xanthogranulomatous cholecystitis (XGC). MATERIAL AND METHODS: Patients of 17 XGCs and 43 wall-thickening gallbladder carcinomas (GBCs) were enrolled in this study. Firstly, we compared the ability of conventional ultrasound (CUS) and CEUS in detecting gallbladder (GB) features. Secondly, XGCs and GBCs features were compared on CEUS. Finally, all valuable indicators were ranked by Odds ratio. RESULTS: Significant differences were found in detecting GB wall thickness, GB stones, and hypoechoic nodules frequencies by CEUS and CUS. The mean GB wall thickness was 8.53 mm on CEUS, whereas the thickness measured 9.47 mm on CUS (p=0.011). GB stones and hypoechoic nodules were detected in 43 cases (71.7%) and 21 cases (30.0%) on CEUS, respectively, compared to 29 cases (48.3%) and 8 cases (13.3%) on CUS (p=0.009, p=0.027), respectively. Secondly, hypoenhancement time was longer in XGC (mean 78.9 s) than in GBC (mean 56.0 s) (p=0.002). Diffuse GB wall thickening, continuous inner wall, and hypoechoic nodules in the GB wall were observed in 12 patients (70.6%), 12 patients (70.6%) and 10 patients (58.8%) with XGC, respectively, compared to detection in 10 patients (23.3%), 4 patients (9.3%) and 11 patients (25.6%) by GBC (p=0.001, p=0.000 and p=0.015), respectively. Thirdly, the continuous inner wall was the most valuable indicator, with ORs of 23.4. The second valuable indicator was hypoenhancement time >80.5 s, with ORs of 11.9. CONCLUSIONS: CEUS demonstrated superior detection of GB wall thickness, GB stone and hypoechoic nodules compared to CUS. A continuous inner wall, hypoenhancement times greater than 80.5 s, diffuse thickening, and hypoechoic nodules were valuable indicators in XGCs.