BackgroundDetermining the resectability of pancreatic cancer with vascular involvement on preoperative computed tomography imaging remains challenging, especially following preoperative chemotherapy and chemoradiotherapy. Intraoperative ultrasound (IOUS) may provide real-time additional information, but prospective multicenter series confirming its value are lacking.Patients and MethodsThis prospective multicenter study included patients undergoing surgical exploration for pancreatic cancer with vascular involvement. All patients underwent IOUS at the start of explorative laparotomy. Primary outcomes were resectability status as defined by the National Comprehensive Cancer Network and the extent of vascular involvement.ResultsOverall, 85 patients were included, of whom 74 (87%) were post preoperative chemotherapy, and mostly following FOLFIRINOX regimen (n= 57; 76%). On the basis of preoperative imaging, 34 (40%) patients were staged as resectable (RPC), 32 (38%) borderline resectable (BRPC), and 19 (22%) locally advanced pancreatic cancer (LAPC). IOUS changed the resectability status in 32/85 (38%) patients (p< 0.001), including 8/19 (42%) patients with LAPC who were downstaged (4 to BRPC, 4 to RPC), and 22/32 (69%) patients with BRPC who were downstaged to RPC. Among patients with presumed superior mesenteric artery (SMA) involvement, 20/28 (71%) had no SMA involvement on IOUS. In 15 of these 20 patients a pancreatic resection was performed, all with R0 SMA margin.ConclusionIOUS during surgical exploration for pancreatic cancer and vascular involvement downstaged the resectability status in over one-third of patients, which could facilitate progress during surgical exploration. This finding should be confirmed by larger studies, including detailed pathology assessment.Trial Registrationwww.trialregister.nl(NL7621).Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-023-13112-3.