Pancreatic ductal adenocarcinoma (PDAC) is an important cause of cancer death with no clear prognostic biomarker. Expression of prion (PrP) has been reported to be a marker of poor prognosis in a series of Caucasian PDAC cases. We determined the prognostic value of PrP in a racially and geographically diverse population-based series of PDAC cases. PrP expression was examined in 142 PDAC cases from three cancer registries. Cases included 71 Caucasian, 54 Asian/Pacific Islanders and 17 Blacks diagnosed from 1983–2000, and followed through 2008. Hazard ratios (HR) and 95% confidence intervals (CIs) for the association of PrP expression with survival were computed after adjustment for case attributes. The risk of death was about four times higher (HR=3.8; 95% PDAC cases with PrP+ tumors (median survival 5 months) compared to the 34 cases with PrP- tumors (median survival 20 months). Of 51 cases with resected, localized PDAC median survival was 74 months for 17 cases with PrP- tumors versus 14 months for 34 cases with PrP+ tumors (HR=6.7; 95% CI: 2.6, 17.4). All 6 surviving cases had PrP- negative tumors (median survival, > 10 years). PrP may have potential as a prognostic biomarker in PDAC patient management.