AbstractTwo dideoxynucleosides, 2′,3′-dideoxy-β-L-cytidine and 2′,3′-dideoxy-β-L-5-fluorocytidine, containing unnatural L-configuration in their sugar moieties, were synthesized and assayed for antiviral activities. Both compounds were shown to possess potent anti-human immunodeficiency virus type 1 and anti-hepatitis B virus activities, while demonstrating no anti-herpes simplex viruses 1 and 2 activity. These two compounds exhibitedin vitrocellular toxicities for several leukocytic cell lines and were shown to inhibit phytohemagglutinin-stimulated human peripheral blood mononuclear leukocyte proliferations. At inhibitory concentrations, both compounds caused accumulations of cells in the S phase. While demonstrating no obvious morphological toxicityin vivoin mice at concentrations of 75 and 150 mg/kg, 2′,3′-dideoxy-β-L-5-fluorocytidine-treated animals were shown to have considerable increases in CD4/CD8double positive T lymphocyte population in their blood circulation.