The capacity of the antibody repertoire to recognize complex antigens on viral-infected cells was investigated at the level of monoclonal B cell responses. A majority of primary B cells responsive to PR8(H1N1)-infected H-2 syngeneic cells produced antibody that bound viral determinants only in the context of infected cells and not the isolated virion. An examination of the fine specificity of such antibodies revealed that most could be distinguished by a panel of cells infected with closely related heterologous H1 influenza strains. Indeed, most antibodies bound hemagglutinin determinants of PR8 exclusively, and few were broadly cross-reactive. An examination of the same antibodies for their recognition of cell surface antigens revealed that the majority recognized MHC-encoded antigenic determinants. Thus, most BALB.K (H-2k) primary B cells responsive to PR8-L919 (H-2k) cells produced monoclonal antibodies that bound PR8-antigens only in the context of H-2Dk-infected cells. Most C57BL/10 (H-2b) B cells responsive to PR8-EL4 (H-2b) cells produced monoclonal antibodies that bound PR8 antigens only in the context of H-2Kb-infected cells. These latter antibodies were further shown to recognize that H-2Kb molecule by virtue of their capacity to be discriminated by a panel of PR8-infected H-2Kb mutant cells. These findings demonstrate that much of the antibody repertoire is capable of highly specific complex recognition of viral antigenic determinants in the context of the appropriate MHC alloantigen.