The possible role of an antibody-dependent cellular cytotoxicity (ADCC)-type mechanism in the passive serum therapy of Friend leukemia virus (FLV)-induced erythroleukemia has been investigated by determining whether successful serum protection requires an intact Fc portion on the administered antibody. F(ab')2 fragments of IgG extracted from chimpanzee anti-FLV and goat anti-FLV gp71 antisera were prepared and compared with whole serum and uncleaved IgG for their capacity to protect DBA/2 mice against challenge with leukemogenic dose of FLV. Despite demonstrating in vitro virus neutralizing activity equivalent to that seen with antiviral serum or IgG, the virus-specific F(ab')2 preparations were devoid of protective activity. Given that passively administered F(ab')2 of goat origin have been reported to persist at stable levels in the mouse circulation, the failure of these F(ab')2 preparations to protect against virus challenge cannot be ascribed to rapid clearance from the treated animals. These results indicate that the passive serum therapy of FLV-induced disease is Fc dependent, consistent with the involvement of an ADCC-type mechanism, as well as confirming the previous suggestion that virus neutralization does not represent the sole mechanism of serum protection in this system.