Prion diseases are infectious fatal neurodegenerative diseases caused by misfolded, aggregated formed of the prion protein, often referred to as prions or PrPSc. The most common form of human prion disease is sporadic Creutzfeldt-Jakob disease (sCJD) that presents itself as several subtypes, and the best characterized of those are the MM1 and MM2 subtypes. Earlier studies, including those from our lab revealed that all the phenotypic variation of MM1 and MM2 cases is closely related to (and likely encoded in) differences in structural organization of corresponding prions. However, this comparison was limited to very low-resolution studies, lacking crucial structural details. The recent development of cryo-EM methods for structural studies of other disease-related protein aggregates have revolutionized the field of prion structural biology, providing high-resolution structures of many pathogenic protein aggregates. Currently, no information is yet available about high-resolution structure of sCJD prions. In this study we aim to fill this critical gap in the field, by determining high-resolution structures of phenotypically well-characterized MM1 and MM2 sCJD prions. Such information is of fundamental importance not only for understanding the molecular basis of phenotypic variability of sCJD but also for the development of therapeutic approaches against human prion diseases.