Background: Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid β (Aβ) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation. Objective: To characterize a family with CJD in which Aβ plaques codistribute with spongiform degeneration. Design: Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype. Setting: Alzheimer disease research center. Participants: Two generations of a family. Main Outcome Measures: Clinical, biochemical, and neuropathologic observations in 2 generations of a family. Results: In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aβ plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE ε4 carrier but not in the APOE ε4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children. Conclusions: To our knowledge, this is the first description of Aβ plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely influence each other. The kindred described herein provides support that PrP E200K may result in increased Aβ deposition.