Novel L-lyxo-TSAO-T analogs with an inverted configuration at the C-4'-position of the sugar moiety and 5'-deoxy-5'-modified TSAO-T derivatives have been prepared and evaluated for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication in cell culture. None of the compounds showed marked antiviral efficacy. The inactivity of the TSAO-T derivatives may most likely be explained by either their different 4'-configuration or their different chemical structure that may not allow an optimal interaction of the molecules with the lipophilic binding pocket of the HIV-1 reverse transcriptase.