Background: The use of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) is increasing. While there is an association between NAT and improved post-pancreatectomy complication rates in limited patient populations, the strength of the relationship and its applicability to a broader and modern pancreatectomy cohort remains unclear. Methods: We used the 2014–2018 American College of Surgeons National Surgical Quality Improvement Project to evaluate NAT use for PDAC patients undergoing pancreatectomy. We also used propensity score matching techniques to compare 30-day postoperative outcomes, including clinically relevant postoperative pancreatic fistula (CR-POPF) and delayed gastric emptying (DGE), between patients selected for NAT versus upfront surgery. Results: Patients receiving NAT were more likely to undergo vascular resections (33% vs. 16%, p < 0.001), have perioperative transfusions (18% vs. 12%, p < 0.001), and undergo longer procedures. Rates of CR-POPF (6%, vs. 10%, p < 0.001), DGE (11% vs. 13%, p = 0.016), postoperative percutaneous drainage (9% vs. 12%, p < 0.001), and SSI (15% vs. 18%, p < 0.001) were lower for patients selected for NAT. The association of NAT with CR-POPF remained statistically significant (adjusted odds ratio 0.52, 95% CI 0.42–0.66) after adjustment for operative technique, gland texture, and need for vascular resection for patients undergoing pancreaticoduodenectomy, but not for patients undergoing distal pancreatectomy. Conclusions: Among PDAC patients undergoing resection, selection for NAT is associated with fewer CR-POPFs, postoperative procedural interventions, and infectious complications, particularly for patients undergoing pancreaticoduodenectomy. These associations should be considered in discussions of multidisciplinary treatment sequencing for patients with PDAC.
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