Background: The management of borderline resectable pancreatic cancer (BRPC) remains unsettled and the predictors of outcome are uncertain. We evaluated the role of neoadjuvant therapy (nRx) and outcomes in patients with BRPC. Methods: We conducted a retrospective cohort study of consecutive patients with BRPC who received nRx and were followed at the Cleveland Clinic. A histopathologic diagnosis of pancreatic carcinoma was required. Tumor anatomy was assessed by contrast-enhanced cross-sectional imaging (CT or MRI), and BRPC was defined as a tumor-vessel wall interface involving one or more of: celiac artery, superior mesenteric artery, common hepatic artery, main portal vein, superior mesenteric vein; making margin-negative resection unlikely. Baseline laparoscopy was performed to rule out occult metastatic disease. Chemotherapy (CT), radiation (RT), surgery details, and pathologic and survival outcomes were evaluated. Hazard ratios (HR) with 95% confidence intervals (CI) and 2-sided p-values are presented. Results: The study population comprised 79 patients from 2009 to 2014. Median age was 64 years; 52% were male; 85% were Caucasian. Pancreatic head/neck were the primary site in 81%; body/tail in 19%. Vascular involvement included arterial in 32 (41%), and venous in 65 (82%) patients. nRx included RT in all patients; 77 (97%) received CT; gemcitabine (n = 50, 63%) was the most common agent. After CT/RT, 36 (46%) patients had unresectable/inoperable disease: 29 (37%) for anatomic reasons, 4 (5%) for physiologic reasons, and 3 (4%) for both. Surgical resection was performed in 43 (54%) patients; 38 (88%) had negative margins; 30 (70%) had negative nodes; 32 (74%) received adjuvant CT. There were no statistically significant predictors of resection. After median follow-up of 27 mths, there have been 45 deaths (57%); median overall survival (mOS) is 23.5 mths (95% CI: 16-28 mths). Only cancer resection was associated with survival (mOS, resected: not reached; mOS, not resected: 12.8 mths; HR: 0.30, 95% CI: 0.16-0.56, p = 0.0002). Conclusions: Surgical resection, if feasible, of BRPC is associated with improved OS. Strategies to improve the odds of resection should be evaluated in prospective studies.