Background: As neoadjuvant therapy of locally advanced, borderline resectable pancreatic cancer (BRPC) is becoming more widely utilized; better indicators of progression are needed to help guide therapeutic decisions. The aim of this study is to determine if CA19-9 response during treatment predicts disease progression. Methods: A retrospective review was performed on all patients with BRPC (by AHPBA/SSO consensus criteria) between 2008-2015 who received 24 weeks of neoadjuvant gemcitabine and docetaxel. Patients with medical comorbidities limiting treatment completion were excluded. Serum CA19-9 levels were checked at baseline and every 3 weeks while on therapy. A normal CA19-9 level was defined as < 37.5 units/mL and levels with concomitant biliary obstruction were censored. CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. Results: Eighty patients were included with a mean of 11 CA19-9 levels checked per patient during treatment. Thirty-two (40%) progressed on treatment (18 local and 14 distant) and 48 (60%) were resected (79% R0). CA19-9 responses were categorized into 5 groups: 1) Always normal [n = 13]; 2) Increasing [n = 3]; 3) Slow decline [n = 7]; 4) Rapid decline with plateau [n = 41]: and 5)Rapid decline with late rise [n = 16]. Univariate logistic regression analysis found that a final CA19-9 decline > 50% of baseline (OR 0.06, p = <.0001), a normal final CA19-9 (OR 0.08, p = <.0001), pattern group 1 (OR 0.16, p =.0001), and group 4 (OR 0.10, p =.0001) were predictive of non-progression. Baseline or maximum CA19-9 levels were not predictive of progression. All patients in group 2 progressed; none were resected. Patients in pattern group 5 that underwent resection had an increased risk of recurrence (HR 12.5, p =.0005). Median overall survival for groups 1-5 were 20.4, 9.3, 20.8, 31.4, and 16.4 months respectively. Conclusions: Patients with measurable CA19-9 levels who do not have rapid decline with sustained low or normal levels should be considered high risk for progression or recurrence and alternative treatment strategies should be entertained prior to curative resection.