Conversion of cellular prion protein (PrP^C) into a pathological conformer (PrP^Sc) is thought to be promoted by PrP^Sc in a poorly understood process. Here, we report that in wild-type mice, the expression of PrP^C rendered soluble and dimeric by fusion to immunoglobulin Fcγ (PrP-Fc₂) delays PrP^Sc accumulation, agent replication, and onset of disease following inoculation with infective prions. In infected PrP-expressing brains, PrP-Fc₂ relocates to lipid rafts and associates with PrP^Sc without acquiring protease resistance, indicating that PrP-Fc₂ resists conversion. Accordingly, mice expressing PrP-Fc₂ but lacking endogenous PrP^C are resistant to scrapie, do not accumulate PrP-Fc₂^Sc, and do not transmit disease to others. These results indicate that various PrP isoforms engage in a complex in vivo, whose distortion by PrP-Fc₂ affects prion propagation and scrapie pathogenesis. The unique properties of PrP-Fc₂ suggest that soluble PrP derivatives may represent a new class of prion replication antagonists.