Antibody-dependent cellular cytotoxicity (ADCC) was analysed in groups of cynomolgus monkeys that had been immunized with either HIV-2 (strains SBL6669 or SBL-K135) or SIVmac. HIV-2- and SIVmac-infected monkeys were also studied for ADCC. Sequential serum samples were collected from the animals, which were followed for 1 to 3 years. Sera from the HIV-2-immunized monkeys had ADCC against both homologous and heterologous HIV-2 strains as well as cross-reactivity against SIVmac-infected target cells. This broadly reactive ADCC response could be detected within the first weeks after immunization. Homologous ADCC was also seen in seven of eight SIVmac-immunized monkeys which were all protected from later challenge with SIVmac or SVsm. ADCC titres sometimes decreased after a few months if the immunized monkeys were not boosted whereas most of the HIV-2-and SIVmac-infected monkeys developed a rapid and persistent ADCC response. The presence of ADCC, like the presence of neutralization in previous studies, did not predict whether the immunized monkeys would be protected upon challenge with live virus.