Tumor cells infected by Epstein–Barr virus (EBV) express latency proteins, among which LMP1 is able to increase the level of the anti‐apoptotic protein BCL‐2, today considered as an attractive target for therapeutic strategies. Our results suggest that agents targeting BCL‐2, used either alone or in combination with rituximab, represent a novel promising approach for post‐transplant EBV‐positive B lymphoproliferative disorder treatment. Post‐transplant lymphoproliferative disorders (PTLD) and Burkitt's lymphoma (BL) are B‐cell malignancies strongly associated with Epstein–Barr virus (EBV) infection. In these lymphoproliferative disorders, EBV infection induces an increase in the expression of the anti‐apoptotic protein BCL‐2. Given its chemoprotective effect, BCL‐2 constitutes an attractive target for new therapeutic strategies for EBV‐positive B‐cell malignancies. Here, we show that ABT‐737, a small inhibitor of BCL‐2, BCL‐X(L), and BCL‐w, strongly induced apoptosis in vitro in EBV‐positive lymphoblastoid cell lines (which is a model for PTLD), whereas BL was less sensitive. ABT‐737 reduced tumor growth and increased the overall survival of mice in a xenograft model of PTLD but had no effect on BL xenograft mice. ABT‐737 combined with a low dose of cyclophosphamide, a major component of the conventional CHOP chemotherapy regimen for BL patients, reduced tumor growth during treatment but failed to improve the overall survival of BL xenograft mice. By contrast, the combination of ABT‐737 and rituximab, one of the main options for the treatment of PTLD, was highly efficient and induced approximately 70% remission in PTLD xenograft mice. These results suggest that the use of agents targeting BCL‐2, either alone or in combination with other conventional drugs, represents a novel promising approach for post‐transplant EBV‐positive B lymphoproliferative disorders.