The potent capacity of B6 anti-AD755a tumor cell serum to protect mice against challenge with large doses of the homologous tumor cells has been shown to reside in the IgG2a antibody subclass. Despite their inability to protect in vivo, other IgG subclass antibodies obtained from the anti-AD755a serum demonstrated serologic reactivities in vitro comparable to those obtained with the protective IgG2a fraction. The specificity of serum protection is linked to the oncornavirus associated with the AD755a tumor and the serum immunoprecipitates only virus structural proteins from the tumor cell surface. Removal of these antibodies by specific immunoadsorbent resins eliminated nearly all of the in vitro serologic reactivity of unfractionated serum and the IgG2a subclass, but it had absolutely no effect on their protective capacity in vivo. Further target cell-binding studies suggest that nonprotective antibodies in the anti-AD755a serum bind more efficiently to the target cell in vitro than the protective fraction and have raised the possibility that the latter antibodies may only have weak affinity for the target cell itself.