More than 200 sera from macaques immunized with several different vaccine preparations were tested in various assays with cells of human and macaque origin. Only in instances where whole inactivated SIV preparations were used for immunization, were reactivities found with normal human cells, and this was the case in every instance. Such sera produced a marked clumping of several normal human cell lines and exhibited strong staining of the cell surface in FACS analysis. In the presence of SIVDeltaB670, these sera also enhanced infectivity and fusion formation. When similar tests were performed with macaque cells as targets, such phenomena were not easily discernible. Likewise, there was no trace of such activities in sera from normal animals, animals chronically infected with SIV, or in those from animals which received recombinant viral subunits as vaccines. Finally, we show that in several instances where whole inactivated virus was used as a vaccine, there is a strong correlation between the titer of anticellular activity with protection.