Prion diseases are a unique group of invariably fatal, infectious, neurodegenerative disorders that can affect animals and humans. After intravenous (IV) prion exposure studies in mice show that the early accumulation and replication of the prions upon stromal follicular dendritic cells (FDC) within the B cell follicles is essential to establish host infection. How infectious prions are initially conveyed from the blood-stream to the FDC in the spleen is uncertain. Addressing this issue is important as treatments that block the early accumulation of prions upon FDC can also block or reduce susceptibility to peripheral prion infections. The marginal zone (MZ) in the spleen contains specialized subsets of B cells and macrophages that are strategically positioned to continuously monitor and remove pathogens, toxins and apoptotic cells from the blood-stream. The continual shuttling of MZ B cells between the MZ and the B-cell follicle enables them to efficiently capture and deliver blood-borne antigens and antigen-containing immune complexes to splenic FDC. We tested the hypothesis that MZ B cells play a similar role in the initial shuttling of blood-borne prions to FDC. MZ B cells were temporarily depleted from the MZ by antibody-mediated blocking of integrin function. We show that the absence of MZ B cells around the time of IV prion exposure did not affect the early accumulation of blood-borne prions upon splenic FDC or reduce susceptibility to IV prion infection. In conclusion, our data suggest that the initial delivery of blood-borne prions to FDC in the spleen occurs independently of MZ B cells.