Background: Neoadjuvant approaches are routinely used in the treatment of resectable, borderline resectable (BR) and locally advanced (LA) PDAC. However, there are few predictive biomarkers of response to neoadjuvant therapy in potentially resectable PDAC patients. Mutations in DDR genes occur frequently in PDAC; however, their implications in PDAC in the neoadjuvant setting remain unclear. Methods: We conducted a dual center (Cedars-Sinai and MGH), matched cohort retrospective analysis of patients with resectable, BR or LA PDAC with and without DDR mutations (ATM, BARD1, BRCA1, BRCA2, CHEK2, CDKN2A, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, PALB2, PMS2, STK11, TP53) who received neoadjuvant therapy. The Fisher’s exact test or Chi square test was used for categorical variables and long-rank test for disease-free survival (DFS) and overall survival (OS). Results: A total of 104 patients were included, of which 52 had a pathogenic germline mutation in a DDR gene (DDR-positive) and 52 had no pathogenic germline mutations (DDR-negative). Median age was 63 years, 53% (n=55) were male, 93% (n=97) received FOLFIRINOX as first-line neoadjuvant therapy. At diagnosis, 24% (n=25) of patients had resectable stage, 39% (n=41) had BR stage and 37% (n=38) had LA stage. Between the two groups, there was no difference in median age, sex, neoadjuvant regimen or stage (all p≥0.4). The rate to surgical resection was 73% for the DDR-positive group vs. 71% for the DDR-negative group (p>0.99). When classified by surgical stage, there was no difference in rate to surgical resection between the two groups, with DDR-positive and DDR-negative rates, respectively, of 100% and 92% (p=0.29) for resectable patients, 95% and 90% (p=0.58) for BR patients and 32% and 37% (p=0.73) for LA patients. Only 4 patients, all DDR-positive, achieved a complete pathologic response. The pathologic complete or near complete response rate was 47.2% (n=17) for the DDR-positive patients vs. 25.7% (n=9) for the DDR-negative patients (p=0.06). The median DFS was not reached for the DDR-positive patients vs. 10.8 months for DDR-negative patients (HR 0.37; p = 0.002). The median OS was 88.3 months for the DDR-positive group vs. 41.3 months for the DDR-negative group (HR 0.55; p=0.04). For resected patients, the median OS was 88.3 months for DDR-positive group vs. 57.1 months for the DDR-negative group (HR 0.45; p=0.048). For non-resected patients, median OS was 25.3 months for the DDR-positive group vs. 15.2 months for the DDR-negative group (HR 0.51; p=0.09). Conclusions: This study demonstrated that patients with resectable, BR or LA-PDAC with germline DDR mutations have a significantly prolonged DFS and OS and increased complete or near complete pathologic response rates. This suggests increased benefit from neoadjuvant therapy across all potentially resectable patients with germline DDR mutations.