Previous studies have suggested that the passive therapy of Friend leukemia virus (FLV)-induced disease with chimpanzee anti-FLV serum operates by reducing the level of infectious virus in the treated animal below the immunosuppressive threshold, thereby allowing the host to mount anti-viral immune responses which are responsible for long-term protection. The present study was undertaken to examine directly the effect of passive serum therapy on the marked immunosuppression induced by FLV in progressively infected mice, as well as to determine whether virus-specific host cellular immune effector functions are augmented in serum-protected animals. Using a variety of assays of host immunocompetence, including natural killing (NK), antibody-dependent cellular cytotoxicity (ADCC) in vivo and in vitro induction of allogeneic killers, and mitogen blastogenesis, a marked compartmentalization of FLV immunodepression was observed in progressively infected DBA/2 mice, possibly reflecting the distribution of FLV target cells in various host lymphoid populations. Thus, spleen-cell functions were suppressed most rapidly and to the greatest degree, followed by peritoneal cells and peripheral blood lymphocytes, while lymph node cells and thymocytes maintained normal levels of activity. In contrast, serum-protected mice demonstrated no sign of FLV-induced immunosuppression regardless of the host effector-cell population or immune function examined. However, we were not able to identify host anti-viral cellular immune functions which are significantly enhanced in serum-protected animals; thus the specific role of the host immune system in the passive serum therapy of FLV-induced disease remains undefined at the present time.