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Congo red (CR) has been shown to inhibit the accumulation in scrapie‐infected cells of prion protein (PrP) in the abnormal protease‐resistant form (PrP‐res). However, it was not clear if this effect was due to a direct interaction of CR with either PrP‐res or its protease‐sensitive precursor (PrP‐sen) or to a less direct effect on living cells. Here we show that CR inhibits PrP‐res formation in a simple cell‐free reaction composed predominantly of purified PrP‐res and PrP‐sen. Structurally modified CR analogues were also compared in both the cell‐free conversion reaction and scrapie‐infected neuroblastoma cells. Methylation of the central phenyl groups at the 2,2′ positions diminished the inhibitory potency by ≥10‐fold. In contrast, there was little effect of 3,3′ methylation of the phenyls, deletion of one phenyl, or addition of an amido group between the phenyls. The relative activities of these compounds were well …