Nystatin-A was compared with Amphotericin-B, AZT and foscarnet for their respective abilities to inhibit the replication of human immunodeficiency virus (HIV-1) in H9 cells. Nystatin-A and Amphotericin-B are polyene macrolide antibiotics. Foscarnet, a trisodium phosphonoformate and AZT are the inhibitors of reverse transcriptase (RT). HIV-1 infected H9 cells were cultured for seven days in the presence of all these drugs,at various concentrations and RT activity and p24 antigen production were quantitated. Untreated, HIV-1 infected H9 cells served as controls. Nystatin-A inhibited viral replication most effectively at 10 microg/ml, a concentration that did not affect cell viability. Nystatin-A treatment inhibited RT activity by 95% and p24 production by 90%. These levels of inhibition were comparable to that mediated by Amphotericin B AZT and foscarnet. Western blot analysis of the HIV-infected H9 cells treated with these drugs did not detect any viral protein at the cellular level. These findings were further corroborated by indirect immunofluorescence studies using monoclonal anti-gp120 FITC-conjugated antibodies, and by polymerase chain reaction analysis using a 32P-labeled probe. These results suggest that Nystatin-A merits attention as an antiviral drug for the treatment of HIV-1 infection. In-vivo drug delivery by liposome encapsulation is currently under study. Cerulenin, an inhibitor of fatty acid and sterol synthesis, has been shown to inhibit the HIV replication in H9 cells by 50%. Cerulenin was highly toxic to cells even at 2 ug/ml concentration. The synthetic peptide analog of HIV-protease, SKF-108922 was also shown to have an inhibitory effect on HIV-replication. Both of these agents will be incorporated in to immunoliposomes and future experiments will focus on delivering these agents with greater specificity to reduce toxicity. Haldol, (haloperidol) a closely related compound and known antipsychotic agent, was chosen for testing. Haloperidol inhibits the HIV-1 and HIV-2 proteases in a concentration dependent manner.