Summary: The rates of microscopic incomplete resections (R1/R0CRM+) in patients receiving standard pancreaticoduodenectomy for PDAC remain very high. One reason may be the reported high rates of mesopancreatic fat infiltration. In this large cohort study, we used available histopathological specimens of the retropancreatic fat and correlated high resolution CT-scans with the microscopic tumor infiltration of this area. We found that preoperative MDCT scans are suitable to detect cancerous infiltration of this mesopancreatic tissue and this, in turn, was a significant indicator for both incomplete surgical resection (R1/R0CRM+) and worse overall survival. These findings indicate that a neoadjuvant treatment in PDAC patients with CT-morphologically positive infiltration of the mesopancreas may result in better local control and thus improved resection rates. Mesopancreatic fat stranding should thus be considered in the decision for neoadjuvant therapy. Background: Due to the persistently high rates of R1 resections, neoadjuvant treatment and mesopancreatic excision (MPE) for ductal adenocarcinoma of the pancreatic head (hPDAC) have recently become a topic of interest. While radiographic cut-off for borderline resectability has been described, the necessary extent of surgery has not been established. It has not yet been elucidated whether pre-operative multi-detector computed tomography (MDCT) staging reliably predicts local mesopancreatic (MP) fat infiltration and tumor extension. Methods: Two hundred and forty two hPDAC patients that underwent MPE were analyzed. Radiographic re-evaluation was performed on (1) mesopancreatic fat stranding (MPS) and stranding to peripancreatic vessels, as well as (2) tumor diameter and anatomy, including contact to peripancreatic vessels (SMA, GDA, CHA, PV, SMV). Routinely resected mesopancreatic and perivascular (SMA and PV/SMV) tissue was histopathologically re-analyzed and histopathology correlated with radiographic findings. A logistic regression of survival was performed. Results: MDCT-predicted tumor diameter correlated with pathological T-stage, whereas presumed tumor contact and fat stranding to SMA and PV/SMV predicted and correlated with histological cancerous infiltration. Importantly, mesopancreatic fat stranding predicted MP cancerous infiltration. Positive MP infiltration was evident in over 78%. MPS and higher CT-predicted tumor diameter correlated with higher R1 resection rates. Patients with positive MP stranding had a significantly worse overall survival (p = 0.023). Conclusions: A detailed preoperative radiographic assessment can predict mesopancreatic infiltration and tumor morphology and should influence the decision for primary surgery, as well as the extent of surgery. To increase the rate of R0CRM− resections, MPS should be considered in the decision for neoadjuvant therapy.