Protein quality control degradation systems rid the cell of aberrant proteins, preventing detrimental effects on normal cellular function. Although such systems have been identified in most subcellular compartments, none have been found in the nucleus. Here, we report the discovery of such a system in Saccharomyces cerevisiae. It is defined by San1p, a ubiquitin-protein ligase that, in conjunction with the ubiquitin-conjugating enzymes Cdc34p and Ubc1p, targets four distinct mutant nuclear proteins for ubiquitination and destruction by the proteasome. San1p has exquisite specificity for aberrant proteins and does not target the wild-type versions of its mutant substrates. San1p is nuclear localized and requires nuclear localization for function. Loss of SAN1 results in a chronic stress response, underscoring its role of protein quality control in the cell. We propose that San1p-mediated degradation acts as the last line of proteolytic defense against the deleterious accumulation of aberrant proteins in the nucleus and that analogous systems exist in other eukaryotes.