The macrocyclic polyamines, cyclen and cyclam, and their derivatives have been tested for inhibitory activity against the cytopathogenic effect (CPE) of human immunodeficiency virus type 1 strain HTLV-III_B (HIV-1_IIIB) on CD4⁺ human lymphoblastoma MT-4 cells. Cyclam and its derivatives were complexed with a variety of transition metal ions Ni^II, Zn^II, Cu^II, Fe^III and Co^III. The divalent metal complexes effected lower toxicity and greater anti-HIV-1 activity, while the trivalent metal complexes had no effect on HIV-1-dependent CPE. When dimerized, the anti-HIV activity of monomers was significantly enhanced. A potent inhibition of CPE by biscyclam was transiently observed 4 d after the virus infection, but was not seen at 6 d due to severe toxicity. The toxicity of biscyclam, referred to as delayed toxicity, could be overcome by a metal complexation. The strain specificities of biscyclams were further studied by testing their effects on syncytium formation between HIV-infected and uninfected human acute lymphoblastic leukemia MOLT-4 cells. The 50% inhibitory concentrations of biscyclams against HIV-2_GH-1-dependent syncytium formation were less than one hundredth those for the other HIV strains (HIV-1_IIIB, HIV-1_RF and HIV-1_SF-2).