Objective To explore the value of double contrast enhanced ultrasound (D-CEUS) in detection of periampullary lesions. Methods Clinical data of 43 patients with periampullary lesions who received examinations of D-CEUS and contrast-enhanced magnetic resonance imaging (MRI) both in the Third Affiliated Hospital of Sun Yat-sen University from July 2006 to December 2012 were analyzed retrospectively. The informed consents of all patients were obstained and the ethical committee approval was received. There were 29 males and 14 females with a mean age of (56±2) years old. There were totally 45 lesions in 43 patients, including 30 malignant lesions (13 duodenal papillary carcinomas, 7 distal common bile duct carcinomas, 6 pancreatic uncinate process carcinomas, 4 ampullary carcinomas) and 15 benign lesions which all were distal common bile duct stones. All the lesions were conifrmed by surgical pathological biopsy or choledochoscope. The detection rates of periampullary lesions and the display rates of relation between periampullary malignant lesions and surrounding tissues by D-CEUS and contrast-enhanced MRI were compared. The rates of 2 groups were compared by Chi-square test. Results Periampullary lesions could be displayed clearly both by 2 examination methods. The detection rate of periampullary lesions was 98%(44/45) by D-CEUS and was 96%(43/45) by contrast-enhanced MRI, where no signiifcant difference was observed (χ2=0.345, P>0.05). For the display of relation between periampullary malignant lesions and surrounding tissues, 77%(23/30) was well-deifned, 20%(6/30) was poorly-deifned, and 3%(1/30) was ill-deifned by D-CEUS, while it was 86%(26/30), 7%(2/30), 7%(2/30) by contrast-enhanced MRI accordingly, where no significant difference was observed (χ2=2.517, P>0.05). Conclusions D-CEUS has a high detection rate of periampullary lesions. Its detection ability is similar to contrast-enhanced MRI, and it can be an important supplement to, even a replacement for contrast-enhanced MRI.