Epstein–Barr virus (EBV) is rapidly cleared by the immune system, but it can persist in some cells for life. Under conditions of immunosuppression, B cells that are latently infected with EBV can undergo marked proliferation and malignant transformation. EBV latent membrane protein 1 (LMP1) is essential for the transformation of human B cells. Here, the authors generated a mouse model in which all B cells expressed LMP1. LMP1+ B cells were efficiently deleted by T cells in immunocompetent animals, but they underwent marked clonal expansion and formed large B cell lymphomas in immunocompromised animals. Both CD4+ and CD8+ T cells contributed to immune surveillance of LMP1+ B cells. Natural killer (NK) cells were also activated by LMP1+ B cells, which expressed ligands for the NK cell receptor NKG2D. Indeed, treatment of tumour-bearing mice with an NKG2D–Fc fusion protein caused efficient lysis of LMP1+ tumour cells, suggesting a possible new therapy for EBV-driven B cell lymphomas.