Post-translational modification of the cellular prion protein (PrP(C)) is intimately associated with the pathogenesis of prion disease, yet the normal function of the protein remains unclear. PrP(C) is expressed in lymphoid cells and is known to be a T-cell activation antigen. Further, transcription profiling studies of regulatory T cells have shown preferential overexpression of PrP(C), suggesting a possible role in regulatory function. We report that both the expression of PrP message and cell surface PrP(C) levels are increased in murine CD4(+) CD25(+) regulatory T cells compared with CD4(+) CD25(-) cells. However, PrP(0/0) mice do not show altered regulatory T-cell numbers or forkhead box P3 (Foxp3) expression levels, or impaired regulatory T-cell function in vitro. Nevertheless, the preferential expression of surface PrP(C) by regulatory T cells raises the possibility that therapeutic ligation of PrP(C) might alter immune regulation.