Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a five-year survival rate of only 9%. Analyses based on tumor DNA mutations indicate the presence of specific molecular subtypes of PDAC. Tumor genomic profiling could result in better treatment selection and improved overall survival. We performed a single institution analysis of PDAC mutations and correlated them with clinical outcomes. Methods: PDAC samples from patients (pts) seen at the Lombardi Comprehensive Cancer Center between 2014 and 2018 were profiled using next generation sequencing including 592 whole-gene targets (Caris Life Sciences). Relevant clinical data was mined retrospectively and correlated with genomic data. Pt outcomes were correlated with the presence of mutations in KRAS, MSH2, MSH6, MLH1, PMS2, TP53, SMAD4, CDKN2A, BRCA1, and BRCA2. Results: Our cohort (N = 100) included 50% men and 50% women, 59% were Caucasian and 21% African-American. Thirty-two percent had stage II, 14% had stage III, and 38% had stage IV disease. Seventy-seven percent developed metastatic disease. Genetic mutations were found in KRAS 87% (N = 82), TP53 76% (N = 82), SMAD4 37% (N = 49), CDKN2A 29% (N = 66), and BRCA2 21% (N = 81). Sixty percent of pts with KRAS mutations also had TP53 mutations. Almost all pts with mutated SMAD4, CDKN2A, or BRCA2 also had mutated KRAS (89%, 84%, and 80%). Median overall survival (OS) for all pts from time of diagnosis was 31 months (m). Stratification of OS based on single gene mutations did not significantly impact OS except for CDKN2A. Patients with CDKN2A mutations had significantly reduced OS compared to wild type (22 m vs. 35 m; P = 0.018). OS based on presence of co-occurring mutations only showed a negative OS impact when CDKN2A mutations were present (14 m vs. 35 m; P = 0.021). Conclusions: Our data demonstrate that the presence of CDKN2A mutations is an independent negative prognostic OS indicator for patients with PDAC. This finding highlights the need to select PDAC pts for potential targeted therapies, including those that target the cell cycle pathway (e.g. cyclin-dependent kinase inhibitors).