A series of 2′,3′-dideoxy-4′-thionucleoside analogues of purines and pyrimidines, including 4′-thioddI (17), 4′-thioddC (27), and 4′-thioAZT (34), were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV). A stereospecific synthesis of the 2,3-dideoxy-4-thioribofuranosyl carbohydrate precursor 11 starting with l-glutamic acid is described. 2′,3′-Dideoxy-4′-thiocytidine (27) displayed significant, but modest activity in vitro against human immunodeficiency virus. © 1992, American Chemical Society. All rights reserved.