Various 3'-azido, 3'-amino, 2',3'-unsaturated, 2',3'-dideoxy, and 5-substituted analogues of pyrimidine deoxyribonucleosides have been prepared and tested against Moloney-murine leukemia virus (M-MULV), a mammalian T-lymphotropic retrovirus in vitro. Among these compounds, the 3'-azido analogues of thymidine, 2'-deoxy-5-bromouridine, and 2'-deoxy-5-iodouridine, the 2',3'-unsaturated analogue of thymidine and and 2'-deoxycytidine, and 2',3'-dideoxycytidine were found to be most active, with ED50 values of 0.02, 1.5, 3.0, 2.5, 3.7, and 4.0 microM, respectively. These active compounds were nontoxic to the host SC-1 cells up to 100 microM concentration. The 3'-azido analogues of thymidine and 2'-deoxy-5-bromouridine were also tested in vitro against HTLV-III/LAV/AAV ("AIDS" virus) and found to be significantly active, with ED50 values of 0.23 and 2.3 microM, respectively. The structure-activity relationships are discussed.