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Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrPSc). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrPC) into infectious PrPSc. By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrPSc. In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrPC allotype to PrPSc in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrPSc with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrPC containing an M or V at residue 129 having a similar propensity to misfold into PrPSc thus causing sCJD. By contrast, PrPSc with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrPSc containing V at residue 129. In both types of CJD, the PrPSc allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrPSc allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD., Author Summary In Creutzfeldt-Jakob disease (CJD), heterozygosity at residue 129 for methionine or valine in normal prion protein may affect disease phenotype, onset and progression. However, the relative contribution of each prion protein allotype to the infectious, disease associated form of prion protein (PrPSc) is unknown. Here we report the novel observation that in heterozygous cases of sporadic CJD the PrPSc allotype ratio is highly variable. This case-by-case variability is consistent with the origin of sporadic CJD being the spontaneous, but random, misfolding of either host prion protein allotype into infectious PrPSc. By contrast, in heterozygous cases of iatrogenic CJD in the United Kingdom resulting from exposure to contaminated human growth hormone, the PrPSc allotype ratio is much more homogeneous and consistent with exposure to infectious PrPSc containing valine at residue 129. Surprisingly, the PrPSc allotype ratio did not correlate with disease onset or duration in either disease type. Thus, factors other than PrPSc allotype ratio likely influence the clinical progression of heterozygous cases of CJD. Moreover, our results suggest that the ratio of methionine to valine in PrPSc may be a means of determining the origin of prion infection.