Objective: We analyzed perioperative outcomes of patients undergoing pancreatectomy with portal vein resection for pancreatic cancer using temporary intraoperative mesoportal or mesocaval bypass. Summary Background Data: Pancreatectomy for advanced pancreatic cancer with long-segment involvement or complete occlusion of the mesoportal venous axis and cavernous transformation represents a major technical challenge. To avoid major bleeding as well as to overcome severe bowel congestion or ischemia due to long portal venous clamping, a mesoportal or mesocaval venous bypass graft first approach has been proposed. If an additional hepatic arterial resection needs to be considered, the mesoportal bypass seems preferable to ensure portal venous flow avoiding complete temporary vascular exclusion of the liver. However, the mesocaval approach appears to be a technically easier alternative. Methods: All consecutive patients who underwent pancreatectomy with venous bypass were identified from a prospectively maintained database. Patient characteristics, perioperative data, and postoperative short-term outcomes were analyzed. Results: Between 2011 and 2024, 63 patients were operated with temporary construction of an alloplastic venous bypass, including 34 patients with mesoportal and 29 patients with mesocaval bypass. Severe complications (Clavien-Dindo >3a) occurred in 16 of 63 patients (25.4%). No postoperative liver failure was observed. The median length of ICU and hospital stays were 2 and 21 days, respectively. The 90-day mortality rate was 6.3%. There were no differences in complication rates, median length of stays, and 90-day mortality rates between mesoportal and mesocaval shunts. Conclusions: Temporary intraoperative venous bypass graft first techniques are important surgical approaches for safe resection of advanced pancreatic tumors. Mesoportal and mesocaval shunts are both safe with comparable postoperative morbidity and mortality rates. The decision for mesoportal versus mesocaval bypass should be made according to the anatomy, particularly taking into account the extent of arterial involvement and the potential need for concomitant arterial resection.