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Epstein-Barr virus (EBV)–specific T-cell preparations, generated by stimulating immune donor lymphocytes with the autologous virus-transformed B-lymphoblastoid cell line (LCL) in vitro, can be used to target EBV-positive malignancies. Although these preparations are enriched for EBV antigen–specific CD8+T cells, most also contain a CD4+T-cell population whose specificity is unknown. Here, we show that, although CD4+T-cell clones derived from such cultures recognize HLA class II–matched LCLs but not mitogen-activated B lymphoblasts, many (1) do not map to any known EBV antigen, (2) can be raised from EBV-naive as well as EBV-immune persons, and (3) can recognize a broad range of human B lymphoma–derived cell lines irrespective of EBV genome status, providing those lines to express the relevant HLA class II–restricting allele. Importantly, such CD4+clones not only produce IFNγ but are also cytotoxic and can control the outgrowth of HLA-matched lymphoma cells in cocultivation assays. We infer that such CD4+T cells recognize cellular antigens that are preferentially up-regulated in EBV-transformed but not mitogen-activated B lymphoblasts and that are also expressed in a range of B-cell malignancies. Such antigens are therefore of potential value as targets for CD4+T cell–based immunotherapy.