Ten healthy adult cynomolgus monkeys (Macaca fascicularis) were inoculated with two different isolates of human immunodeficiency virus type 2 (HIV-2), SBL-6669 and SBL-K135, to establish an animal model for HIV infection. HIV-2SBL-6669 had been propagated for a long time in continuous human cell lines whereas HIV-2SBL-K135 had been grown only in fresh human and monkey lymphocyte cultures or previously for a short time in a continuous cell line. Virus was isolated from three or four animals inoculated with HIV-2SBL-K135 but in none of six monkeys inoculated with HIV-2SBL-6669. All animals seroconverted although the antibody response was higher in SBL-K135 virus-infected monkeys. Varying degrees of lymphadenopathy were observed but there were no significant changes in the numbers of CD4+ and CD8+ T cells. The infection was transferred to two monkeys inoculated with blood from a previously SBL-K135 virus-infected monkey. Four animals inoculated with HIV-2SBL-K135, which had never been propagated in continuous human cell lines, showed strong antibody responses against both gag- and env- encoded proteins of HIV-2. None of the SBL-6669 infected monkeys showed antibodies to core proteins. HIV-2 infection of cynomolgus monkeys represents a useful experimental model for HIV vaccine trials and antiviral testing.