Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease of poor prognosis, while secondary brain metastasis (Br-M) is reported to occur in less than 1% of patients with PDAC, with only limited data available suggesting that patients with Br-M have even worse prognosis. We sought to evaluate the prognosis, clinical, and molecular characters of patients with Br-M secondary to PDAC. Methods: The Foundry software platform was used to retrospectively query the electronic health records to identify patients diagnosed with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and oncologic outcome data were collected. Results: Br-M was diagnosed in 44 patients with PDAC. The median follow-up was 78 months for our cohort while median overall survival (OS) from diagnosis was 47 months (95%CI=34-79 months). The median duration for Br-M detection from PDAC diagnosis was 24 months, while median OS from Br-M diagnosis was only 3 months (95%CI=2-6 months). 48% (n=21) had metastatic disease at diagnosis. Histological grade was assessed for 37 patients of which 51% (n=19) patients had poor differentiation, while 46% had moderate differentiation, and only 1 patient had a well differentiated tumor. Most of our patients received multiple lines of chemotherapy prior to Br-M development, with a median of 4 chemotherapy regimens received. The majority (73%, n=32) had ECOG performance score of 0 or 1 at Br-M diagnosis, also 82% (n=36) patients had elevated CA19-9 prior to Br-M. Metastases to more than one site other than the brain were detected in 73% (n=32), lung metastasis was the most frequently detected, followed by liver then bone (71% n=31, 66% n=29, 39% n=17, respectively). The frontal lobe was the most frequently affected (34%, n=15) followed by cerebellar affection (23%, n=10). Leptomeningeal affection was observed in (18%, n=8) patients. Targeted clinical mutation testing was done for 17 patients, KRAS was mutated in 95% (n=16) of patients, with G12V in 47% (n=8) of patients, G12D in 29% (n=5), and G12R in 18% (n=3), the second most prevalent mutation was TP53, 70% (n=12) then CDKN2A in 18% (n=3) of the patients. Surgical resection for Br-M was performed for 5 patients who had better median OS of 8.6 months followed by patients who underwent stereotactic radiosurgery (n=11) with median OS of 3.3 months, and patients who received whole brain radiation (n=20) with median OS of 2.8 months. Conclusions: This is the largest cohort for patients with Br-M form PDAC reporting thatsecondary Br-M is a late complication, associated with extremely poor prognosis, in patients who received multiple lines of therapy and have widely metastatic disease. The frontal lobe is the most frequently affected site. KRAS was the most frequently detected mutation and G12V subtype was more prevalent. surgical resection for Br-M was associated with better OS.