Four protein-based genetic determinants or prions-[SWI(+)], [MCA], [OCT(+)], and [MOT3(+)]-are recent additions to the list of well-known Saccharomyces cerevisiae prions, [PSI(+)], [URE3], and [PIN(+)]. A rapid expansion of this list may indicate that many yeast proteins can convert into heritable prion forms and underscores a problem of prion input into cellular physiology. Here, we prove that the global transcriptional regulator Sfp1 can become a prion corresponding to the prion-like determinant [ISP(+)] described earlier. We show that SFP1 deletion causes an irreversible [ISP(+)] loss, whereas increased SFP1 expression induces [ISP(+)] appearance. Cells that display the [ISP(+)] phenotype contain the aggregated form of Sfp1. Indeed, these aggregates demonstrate a nuclear location. We also show that the phenotypic manifestation of Sfp1 prionization differs from the manifestation of SFP1 deletion. These properties and others distinguish [ISP(+)] from yeast prions described to date.