The efficacy of a recombinant human immunodeficiency virus (HIV) type 2 canarypox (ALVAC HIV-2) vaccine candidate given alone or in combination with HIV-2 envelope gp125 or HIV-2 V3 synthetic peptides was investigated in 14 cynomolgus monkeys. High antibody titers to HIV-2 gp125 were demonstrated in monkeys given booster immunizations with gp125. Neutralizing antibody titers were low (< or = 20) in all monkeys except 2. Significant lymphocyte proliferative responses to killed HIV-2 virions were observed in monkeys given booster immunizations with gp125. HIV-2-specific cytotoxic T lymphocytes were demonstrated prior to viral challenge in 3 of 12 monkeys. After challenge with homologous cell-free HIV-2 propagated in monkey cells, 4 of 10 monkeys immunized with ALVAC HIV-2 plus HIV-2 gp125 or V3 peptides were protected, as determined by negative virus isolation and polymerase chain reaction for viral DNA. Four monkeys immunized with ALVAC HIV-2 alone were not protected. All 12 control monkeys became infected. There was no correlation between the immunologic parameters studied and protection against infection in the vaccinated monkeys.