An oligonucleotide must fulfill two main requirements to become a potential antisense probe: effective hybridization properties with the complementary sequence and stability toward nucleases. In this article the degradation pattern of a new class of potential antisense fragment, (2'S)-2'-deoxy-2'-C-methyloligonucleotides, is analyzed. The results described here show that the modification introduced in these oligonucleotides confers an enhanced stability toward purified nucleases, human sera, and HeLa cell extracts.