Eukaryotic cells possess a special pathway for the degradation of mRNAs containing premature termination codons (PTCs). It is termed nonsense-mediated mRNA decay (NMD). The operation of this pathway in Saccharomyces cerevisiae yeast depends on PTC recognition by the translational machinery and interaction of the eRF1 (Sup45) and eRF3 (Sup35) translation termination factors with the Upf1, Upf2, and Upf3 proteins. Our earlier studies showed that the decrease in eRF1 content in nonsense sup45 mutants resulted in NMD impairment. Here we show that nonsense and missense mutations in SUP35 cause the accumulation of PTC-containing transcripts: his7-1 mRNA and CYH2 pre-mRNA. Thus, sup35 mutations not only decrease translation fidelity but also influence mRNA stability. Remarkably, the deletion of either UPF1 or UPF2 increases the viability of sup35 mutants but UPF3 deletion decreases it.