Background: Intraoperative para-aortic lymph node (PALN) sampling during surgical exploration in patients with suspected pancreatic head cancer remains controversial. Objective: The aim of this study was to assess the value of routine PALN sampling and the consequences of different treatment strategies on overall patient survival. Methods: A retrospective, multicenter cohort study was performed in patients who underwent surgical exploration for suspected pancreatic head cancer. In cohort A, the treatment strategy was to avoid pancreatoduodenectomy and to perform a double bypass procedure when PALN metastases were found during exploration. In cohort B, routinely harvested PALNs were not examined intraoperatively and pancreatoduodenectomy was performed regardless. PALNs were examined with the final resection specimen. Clinicopathological data, survival data and complication data were compared between study groups. Results: Median overall survival for patients with PALN metastases who underwent a double bypass procedure was 7.0 months (95% confidence interval [CI] 5.5–8.5), versus 11 months (95% CI 8.8–13) in the pancreatoduodenectomy group (p = 0.049). Patients with PALN metastases who underwent pancreatoduodenectomy had significantly increased postoperative morbidity compared with patients who underwent a double bypass procedure (p < 0.001). In multivariable analysis, severe comorbidity (ASA grade 2 or higher) was an independent predictor for decreased survival in patients with PALN involvement (hazard ratio 3.607, 95% CI 1.678–7.751; p = 0.001). Conclusion: In patients with PALN metastases, pancreatoduodenectomy was associated with significant survival benefit compared with a double bypass procedure, but with increased risk of complications. It is important to weigh the advantages of resection versus bypass against factors such as comorbidities and clinical performance when positive intraoperative PALNs are found.