Background: As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. Materials and Methods: A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. Results: One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤.0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤.0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1–4 was 58, 16, 20, and 38 months, respectively (p ≤.0001). Conclusion: Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. Implications for Practice: This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.