Recent cases of prion transmission in humans following transfusions using blood donated by patients with asymptomatic variant Creutzfeldt–Jakob disease (CJD) implicate the presence of prion infectivity in peripheral blood. In this study, we examined the levels of the normal, cellular prion protein (PrP C), and the disease-causing isoform (PrP Sc) in subpopulations of circulating white blood cells (WBCs) from patients with sporadic (s) CJD, age-matched neurological controls and healthy donors. Though widely distributed, the highest levels of PrP C were found in a subpopulation of T lymphocytes:∼ 12 000 PrP C molecules were found per CD4+ CD45RA− CD62L− effector memory T helper cell. Although platelets expressed low levels of PrP C on their surface, their high abundance in circulation resulted in the majority of PrP C being platelet associated. Using quantitative fluorescence-activated cell sorting analysis, we found that neither WBC composition nor the amount of cell-surface PrP C molecules was altered in patients with sCJD. Eight different WBC fraction types from the peripheral blood of patients with sCJD were assessed for PrP Sc. We were unable to find any evidence for PrP Sc in purified granulocytes, monocytes, B cells, CD4+ T cells, CD8+ T cells, natural killer cells, nonclassical γδ T cells, or platelets. If human WBCs harbor prion infectivity in patients with sCJD, then the levels are likely to be low.