Histopathologic tumor response to neoadjuvant therapy is associated with improved outcomes in pancreatic cancer. The optimal neoadjuvant regimen remains unclear. We sought to compare response to neoadjuvant chemotherapy alone (CT) or CT combined with radiotherapy (RT). A retrospective review of a single institution database was performed. Patients diagnosed with pancreatic cancer (PCA) between 2009-2018 undergoing neoadjuvant CT, with or without subsequent RT, and definitive surgical resection were included. Resection specimens were assigned a tumor regression grade (TRG) using the College of American Pathologists criteria. TRG scores of 0 (complete response) and 1 (near complete response) were combined for analysis. Clinical and treatment variables associated with TRG were assessed. The impact of TRG on relapse free survival (RFS) was evaluated using the Kaplan-Meier method. Of the 74 patients who met inclusion criteria, 35 were treated with neoadjuvant CT and 39 underwent CT followed by RT. Median FU was 13.3 mos and 95% had borderline resectable or locally advanced PCA. The CT regimen was FOLFIRINOX or Gemcitabine-nab-paclitaxel in 93% of patients. In the RT subgroup, 41% (n=16) received SBRT with a median dose of 36 Gy in 3 fractions; all others received fractionated RT with median dose 50.4 Gy in 28 fractions. The median time from RT to surgery was 1.6 months (IQRT 1.3 – 1.9 mos). The rate of TRG scores of 0-1, 2 (mixed response), and 3 (poor or no response) for the CT group was 11%, 34%, and 54%, respectively, and for the RT group the corresponding rates were 31%, 44%, and 26%, respectively (p=0.02). Seven patients were scored TRG 0 (9%), and the majority (n=6) had received RT. On multivariate logistic regression, RT remained associated with TRG when controlling for CA19-9, age, and initial tumor size (p=0.01). In the RT subgroup, receipt of SBRT, prescribed biological equivalent dose (BED [Gy10]), and min GTV BED were not associated with TRG. As expected, worse TRG was associated with higher lymph node ratio (p<0.01) and positive surgical margins (p=0.03). The association of TRG and RFS trended toward significance (p=0.07); median RFS was not reached in TRG 0-1 and it was 18 mo and 9 mo in TRG 2 and 3, respectively. Compared to neoadjuvant CT alone, neoadjuvant CT followed by RT is associated with greater histopathologic response in PCA.