We present the synthesis and the study of properties of a new series of modified oligonucleotides, namely 4′-thio-oligo-β-D-ribonucleotides (4′-S-RNA). Homo-oligonucleotides of this class (4′-SU6and 4′-SU12) were prepared from the previously known thionucleosides using the phosphoramidite methodology. The comparison of the substrate properties of 4′-SU6and its natural analog U6with respect to four nucleases indicates that the former is much more resistant than the latter. Such resistance to nucleases in addition to relatively high Tm values for 4′-SU6hybridized with Poly(A) show that these new 4′-S-RNA are good candidates for potential antisense effects. The oligonucleotides 4′-SU6and 4′-SU12have been also evaluated as non sequence specific inhibitors of HIV-1 reverse transcriptase. All available evidences, based primarily on fluorescence measurements, are consistent with the binding of 4′-SU6and 4′-SU12to RT at a site which is different from the polymer