ADCC activity in sera from HIV-2-infected individuals was monitored against HIV-1IIIB, SIVmac, and three different HIV-2 strains. The sera mediated ADCC against the HIV-2 strains in high frequencies and reacted equally well with SIVmac, whereas no cross-reactivity was seen against HIV-1IIIB. The degree of antigenic similarities between the virus strains was also evaluated in order to estimate the variability of ADCC target regions. The SIVmac strain and two of the HIV-2 strains were antigenically more similar to each other whereas another HIV-2 strain appeared more distantly related with regard to ADCC target regions. Although strain-specific ADCC was present in some HIV-2-positive sera, HIV-2 ADCC was more broadly reactive and appeared in higher frequencies against these specific strains than has been previously shown for HIV-1 ADCC in a group of four HIV-1 strains. The difference was, however, not significant. To further delineate target regions for ADCC the sera were tested against peptides representing different regions of the HIV-2 envelope protein. The V3 region and the C-terminal end of gp125 were thus suggested to be involved in ADCC. Target regions for HIV-2-specific ADCC may only partly overlap with HIV-2-neutralizing regions since the two activities were not always present in the same sera. Characterization of broadly reacting immune responses like HIV-2-specific ADCC and identification of their specific target epitopes is essential for the development of an efficient AIDS vaccine.