The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression-free survival, and safety/toxicity of neoadjuvant FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty-two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression-free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty-two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC.