Chronic inflammation and immunosuppressive therapies increase the risk of non-Hodgkin's lymphoma associated or not with Epstein-Barr virus (EBV) infection. A possible link between infliximab treatment and increased risk of lymphoma has been suggested. Indeed, infliximab induces apoptosis of monocytes and activated T lymphocytes, but its effect on B lymphocytes infected or not with EBV is unknown. Secreted tumor necrosis factor (TNF) alpha and the expression level of TNF receptor 1 (TNFR1) and TNFR2 were compared in EBV-positive and negative B-cell lines. The impact of TNFalpha and infliximab on apoptosis of EBV-positive cells was analyzed regarding the activity of NF-kappaB. Increased expression of TNFalpha in EBV-positive cells suggested that infliximab could affect their survival. However, TNFalpha or infliximab incubation had no effect on apoptosis of EBV-positive cells. Loss of NF-kappaB activity sensitized lymphoblastoid cell lines to TNFalpha-induced apoptosis, but no direct effect of infliximab on apoptosis was detected. On the basis of our in vitro data, neither TNFalpha nor infliximab has a direct effect on apoptosis of B lymphocytes and EBV-positive cell lines. Thus, if an increased incidence of lymphoma were induced by TNFalpha blockers, it would not involve a direct effect on B cells but rather an impaired immune surveillance by T cells.