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Purpose To evaluate the safety and efficacy of ultrasound-guided percutaneous core needle biopsy (USPCB) of pancreatic and peripancreatic lesions adjacent to critical vessels. Materials and Methods Data were collected retrospectively from 162 patients who underwent USPCB of the pancreas (n = 98), the peripancreatic area adjacent to the portal vein, the paraaortic area adjacent to pancreatic uncinate (n = 34), and lesions on the third duodenal portion (n = 30) during a 10-year period. An automated biopsy gun with an 18-gauge needle was used for biopsies under US guidance. The USPCB results were compared with those of the final follow- up imaging performed postoperatively. The diagnostic accuracy and major complication rate of the USPCB were calculated. Multiple factors were evaluated for the prediction of successful biopsies using univariate and multivariate analyses. Results The histopathologic diagnosis from USPCB was correct in 149 (92%) patients. The major complication rate was 3%. Four cases of mesenteric hematomas and one intramural hematoma of the duodenum occurred during the study period. The following factors were significantly associated with successful biopsies: a transmesenteric biopsy route rather than a transgastric or transenteric route; good visualization of targets; and evaluation of the entire US pathway. In addition, the number of biopsies required was less when the biopsy was successful. Conclusion USPCB demonstrated high diagnostic accuracy and a low complication rate for the histopathologic diagnosis of pancreatic and peripancreatic lesions adjacent to critical vessels. [ABSTRACT FROM AUTHOR]