To investigate the protective efficacy of various gp130 vaccine preparations, rhesus monkeys were immunized with gp130 oligomers (O-gp130) or two different gp130-monomer preparations (M1-gp130; M2-gp130) and challenged with 50 MID50 of simian immunodeficiency virus (SIV)mac32H. Following challenge the control animals and all animals of the M1- and M2-gp130 group and 1 animal of the O-gp130 group were productively infected, whereas 3 animals of the O-gp130 group resisted the productive virus replication. The protection was correlated with high neutralizing antibodies and a long-lasting immune response to the transmembrane protein gp41. Whereas none of the O-gp130 animals had developed disease symptoms, 3 M1-gp130 animals, 1 M2-gp130 animal, and 2 control animals died as a result of AIDS within 18 months after challenge. Therefore, immunization with virion-derived gp130 oligomers of SIVmac32H can confer protection against the productive infection with SIVmac32H and suppress the development of the AIDS-like disease.