OBJECTIVES:: The purpose of this study was to determine the significance of portal vein-superior mesenteric vein (PV-SMV) invasion on survival in patients who underwent margin-negative pancreatoduodenectomy (PD) with PV-SMV resection for pancreatic adenocarcinoma. METHODS:: We retrospectively reviewed the records of 60 patients who underwent margin-negative PD with or without PV-SMV resection for pancreatic adenocarcinoma between August 2001 and December 2007. The depth of vessel invasion was investigated and was categorized into 3 groups: tunica adventitia, media, and intima. Clinicopathologic factors and survival were analyzed. RESULTS:: Portal vein-superior mesenteric vein resection was performed on 19 patients, but only 15 patients (78.9%) had histologically true invasion and showed poorer survival (median survival, 14 vs 9 months; P < 0.05). Univariate analysis revealed that poorly differentiated tumor, lymphatic invasion, endovascular invasion, PV-SMV invasion, and invasion into the intima of PV-SMV were statistically significant. Poorly differentiated tumor and invasion into the intima of PV-SMV were significant in multivariate analysis. CONCLUSIONS:: Aggressive surgical resection should be attempted in cases with suspected PV-SMV invasion because 21.1% of patients had no true invasion and showed better survival than those with true invasion. However, invasion into the tunica intima may be a poor prognostic factor for survival even after margin-negative PD for pancreatic adenocarcinoma.