Background: For patients with localized pancreatic adenocarcinoma, resection and systemic therapy remain the mainstays of curative-intent treatment. Neoadjuvant chemotherapy has been frequently employed with the goals of addressing systemic disease early and improving patient selection for surgery. Those who do not respond to neoadjuvant therapy present a challenge with a lack of randomized data to aid in decision making. Here we sought to define the characteristics and outcomes of those patients to guide clinical practice. Methods: This was a single-institution retrospective cohort study using a prospectively maintained database of those diagnosed with pancreatic adenocarcinoma. Patients included in the study were those who received neoadjuvant chemotherapy. Non-responders were defined as those with both no radiographic and no biochemical response at the first re-assessment after initiation of therapy. Results: A total of 176 patients were identified who were treated with neoadjuvant chemotherapy with curative intent. Of those, 42 (23.8%) patients had no evidence of either radiographic or biochemical response. Of those patients, 14 were upfront resectable (33.3%) and 20 were borderline resectable (47.6%). An additional 8 (19%) were locally advanced. Most patients received FOLFIRINOX as a first line chemotherapy agent (n = 25, 59.5%). A total of 12 (28.6%) patients underwent neoadjuvant radiation therapy. A total of 19 (45.2%) proceeded to surgery and two of those were found to be unresectable at exploration, resulting in 17 (40.5%) who ultimately received curative-intent resection. Exactly half (n = 21) of the patients had their chemotherapy switched (CS). Of those who had CS, 11 (52.4%) had evidence of local tumor progression on their initial restaging scan compared to just 3 (14.3%) of those who did not (p = 0.02). Additionally, patients who had CS had higher incidence of vascular involvement on their initial scan (90.5% vs 52.3%, p = 0.051). A total of 6 (28.6%) who underwent CS had subsequent biochemical response compared 4 (19.0%) of those who did not. Ultimately, 6 (28.6%) of those who had CS ultimately proceeded to surgery compared to 13 (61.9%) of those who did not (p = 0.062). Interestingly, there was no significant difference in median overall survival between those who had CS (18.6 months) and those who did not (19.9 months, p = 0.525). Conclusions: Non-responders to frontline neoadjuvant systemic therapy present a clinical challenge and have poor rates of curative-intent resection. Chemotherapy switch was employed mostly in cases with worse prognostic factors and thus infrequently lead to resection. Despite this, patients who underwent CS had similar overall survival to those who did not. These data suggest there may be a role for chemotherapy switch in those who do not respond to front line chemotherapy.