Termination of protein synthesis in the yeast Saccharomyces cerevisiae occurs when the eukaryotic release factor eRF1 recognises the stop codon. The rate of termination is enhanced by a second release factor, eRF3 (a GTPase). The efficiency of stop codon recognition by eRF1 is influenced by the surrounding nucleotide context of the stop codon, and in yeast, by the structural properties of eRF3, which displays prion-like characteristics. eRF3 in the [PSI⁺], prion state forms insoluble high molecular weight aggregates that cause inefficient termination (nonsense suppression). This study tested the hypothesis that the [PSI⁺] state may direct suppression of stop codons, particularly those in weak contexts. This may confer unique phenotypes upon yeast, particularly stress response phenotypes, caused by C-terminal extension of a subset of proteins. Consistent with this hypothesis, the [PSI⁺] state was found to enhance suppression of all stop codons, with those in weak contexts being most efficiently suppressed. [PSI] is thus a context sensitive suppressor of all three stop codons. Using computer screening, yeast genes whose open reading frames terminate in weak nucleotide contexts were identified as potential candidates for [PSI⁺]-directed stop codon readthrough.