Background <p>Resection of the periadventitial neurolymphatic tissue around the superior mesenteric artery (SMA) is considered a crucial component of oncologically complete resection in pancreatic head and corpus carcinomas. However, a substantial proportion of patients experience severe postoperative diarrhea due to resection of the splanchnic nerves within the SMA-adjacent tissue. The aim of the present study was to histopathologically analyze the semi-circumferential periadventitial neurolymphatic tissue surrounding the SMA in pancreatic cancer patients for the presence of malignant cells, in order to evaluate its oncological significance and to determine whether its resection may confer a long-term survival benefit.</p> Methods <p>A total of 66 patients with resectable malignant tumours of the pancreas treated at the University Medical Centre Göttingen were prospectively enrolled in this exploratory pilot study. The dissected semi-circumferential tissue around the SMA was processed by complete embedding and serial sectioning and analyzed for the presence of malignant cells. Survival analyses were performed using the Kaplan–Meier method with log-rank testing.</p> Results <p>In 7.6% of all cases (<i>n</i> = 5), malignant cells were found in the tissue adjacent to the SMA (SMA⁺). In all SMA⁺-patients, histopathological workup showed a pancreatic ductal adenocarcinoma (PDAC). In 80% of SMA⁺-patients (<i>n</i> = 4), an R1 resection margin was confirmed. Patient outcomes (overall survival [OS] and cancer-specific survival [CSS]) were primarily determined by R-status.</p> Conclusions <p>Malignant SMA-adjacent tissue involvement was identified in 7.6% of resectable pancreatic head tumours and was exclusive to PDAC. R-status appears to be the dominant determinant of survival. These findings should be considered hypothesis-generating and require validation in larger prospective cohorts.</p>