Liposomes are under investigation as carriers of 2', 3'-dideoxynucleotides (ddNT's) in an effort to enhance antiviral activity of these compounds in monocytes-macrophages (M/M) infected with the human immunodeficiency virus type-I (HIV-1). Cells of the M/M lineage are known to play key roles in the dissemination of the virus and pathogenesis of acquired immunodeficiency syndrome (AIDS). The antiviral effects of 2',3'-dideoxycytidine (ddC), 21, 231-dideoxycytidine-5'-triphosphate (ddCTP) and liposomeentrapped ddCTP [L(ddCTP)] were compared in M/M cells infected with HIV-1. These treatments inhibited virus replication at nanomolar drug levels in the order ddC > ddCTP = L(ddCTP). Studies on drug stability and uptake showed that a large portion of ddCTP dephosphorylated before entering cells, whereas L(ddCTP) remained stable over days and was probably taken up by endocytosis. The response to L(ddCTP) suggests that the capabilities of liposomes for targeting drugs to macrophages in vivo can potentially be exploited for improving the therapeutic index of dideoxynucleotide drugs.