We report protease-resistant prion protein (PrPres) in spontaneous lymphoreticular tumors of mice infected with the agent of variant Creutzfeldt-Jakob disease (vCJD). PrPres may accumulate in lymphoreticular system tumors of asymptomatic persons with vCJD. The statistical power of estimates of vCJD prevalence might be increased by expanding screening to include samples of lymphoreticular neoplasms.