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Background: Neoadjuvant therapy-based protocols for potentially resectable pancreatic adenocarcinoma offer theoretical advantages over standard adjuvant therapy-based management. However, these advantages are unproven. The aim of this study was to compare the efficacy of neoadjuvant therapy- and adjuvant therapy-based management using formal decision analysis.Methods: A decision analytic Markov model was created to compare two management strategies for simulated cohorts of patients with potentially resectable pancreatic adenocarcinoma. In the standard strategy, patients undergo surgical resection and subsequently are treated with either adjuvant systemic chemotherapy (CT), chemoradiation therapy (CRT) or both, as tolerated. In the neoadjuvant strategy, patients are treated with an average of 3 months of neoadjuvant therapy (CT, CRT or both) first and then undergo surgical resection (unless disease progression renders them unresectable). Base-case probabilities were derived from published data derived from phase II and III trials (a total 3302 patients with potentially resectable pancreatic cancer were analyzed). The outcome measures were overall and quality-adjusted survival, with survival calculated from date of surgery (adjuvant group) or date when neoadjuvant therapy was initiated. Intention-to-treat analysis was used. Sensitivity analysis was performed to assess the effects of model uncertainty on outcomes. Results: The median overall survivals and 2-year OS rates were 16 months and 30% for patients managed by the standard strategy and 20 months and 42% for those managed by the neoadjuvant strategy, respectively. Quality-adjusted overall survivals for these patients were 13.8 months and 19.6 months, respectively. Sensitivity analysis indicated the benefits of the neoadjuvant strategy over the standard strategy in terms of both OS and quality-adjusted survival are robust: stability of findings is maintained over a wide range of plausible baseline estimates. Conclusions: Our analysis suggests that neoadjuvant therapy-based management improves outcomes of patients with potentially resectable pancreatic cancer. A randomized trial designed to evaluate the advantage of this strategy is warranted.