Background: Developmentally pancreas head derives from ventral bud while pancreas neck, body and tail derive from dorsal bud. Pancreatic ductal adenocarcinoma (PDAC) frequently harbors multiple mutations including KRAS, TP53, CDKN2A, and others. It is unknown how TP53 gain-of-function (GOF) and non-gain-of-function (non-GOF) mutations affect the prognosis. Methods: We retrospectively examined a cohort of 741 Kaiser Permanente (KP) patients with locally advanced/metastatic PDAC who had NGS performed to determine the association of KRAS (mutKRAS), TP53 (mutp53) and CDKN2A (mutCDKN2A) mutations (individually and in combination) with overall survival (OS). We used Cox modeling to estimate hazard ratios (HR) adjusted for age, sex, ethnicity, performance status, Charlston Comorbidity Index, chemotherapy received, anatomic location and co-mutations. We also analyzed the TCGA PDAC dataset to examine the association of OS with these same mutations. Results: In the KP cohort, patient ages ranged from 36 to 94 years and approximately 50% were female. In 384 patients PDAC was on the head, and 357 patients had PDAC on a non-head location (neck, body, and tail). Those with head PDAC had modestly better OS compared to non-head PDAC (HR = 0.87), and this appeared to be driven by the subsets of patients with wtp53 (HR = 0.68), with wtKRAS (HR = .74) and with wtCDKN2A (HR = .78). Approximately 67.5% of patients had mutp53, 89.2% had mutKRAS and 44.8% had mutCDKN2A. Among all KP patients, OS was similar for patients with mutp53 vs. wtp53 (HR = 1.05); worse for patients with mutKRAS vs. wtKRAS (HR = 1.26), and worse for patients with mutCDKN2 vs. wtCDKN2A (HR = 1.51). Interestingly, among patients with a GOF mutp53, those with mutCDKN2A had substantially worse OS vs patients with wtCDKN2A (HR = 2.56, 95% CI 1.46-4.50). In contrast, among patients with a non-GOF mutp53, patients with mutCDKN2A had only moderately worse OS compared to patients with wtCDKN2A (HR = 1.37, 95% CI 1.06-1.79). Analysis of the TCGA PDAC dataset showed that the number of mutations (0, 1, 2, or 3, of p53, KRAS and CDKN2A) was associated with incrementally worse OS (p< .001). Conclusions: Better OS of head vs. non-head PDAC was primarily driven by patients with wtp53, wtKRAS, and wtCDKN2A. The adverse effect of mutCDKN2A on OS appears to be most pronounced in patients with GOF mutp53. Our TCGA analysis suggests interactions among TP53, KRAS and CDKN2A mutations in affecting PDAC survival.