AbstractGenetically predicted proteins have been associated with pancreatic cancer risk previously. We aimed to externally validate the associations of 53 candidate proteins with pancreatic cancer risk using directly measured, prediagnostic levels. We conducted a prospective cohort study of 10 355 US Black and White men and women in the Atherosclerosis Risk in Communities (ARIC) study. Aptamer‐based plasma proteomic profiling was previously performed using blood collected in 1993 to 1995, from which the proteins were selected. By 2015 (median: 20 years), 93 incident pancreatic cancer cases were ascertained. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for protein tertiles, and adjust for age, race, and known risk factors. Of the 53 proteins, three were statistically significantly, positively associated with risk—GLCE (tertile 3 vs 1: HR = 1.88, 95% CI: 1.12‐3.13; P‐trend = 0.01), GOLM1 (aptamer 1: HR = 1.98, 95% CI: 1.16‐3.37; P‐trend = 0.01; aptamer 2: HR = 1.86, 95% CI: 1.07‐3.24; P‐trend = 0.05), and QSOX2 (HR = 1.96, 95% CI: 1.09‐3.58; P‐trend = 0.05); two were inversely associated—F177A (HR = 0.59, 95% CI: 0.35‐1.00; P‐trend = 0.05) and LIFsR (HR = 0.55, 95% CI: 0.32‐0.93; P‐trend = 0.03); and one showed a statistically significant lower risk in the middle tertile—endoglin (HR = 0.50, 95% CI: 0.29‐0.86); by chance, we expected significant associations for 2.65 proteins. FAM3D, IP10, sTie‐1 (positive); SEM6A and JAG1 (inverse) were suggestively associated with risk. Of these 11, 10 proteins—endoglin, FAM3D, F177A, GLCE, GOLM1, JAG1, LIFsR, QSOX2, SEM6A and sTie‐1—were consistent in direction of association with the discovery studies. This prospective study validated or supports 10 proteins as associated with pancreatic cancer risk.