The infection of T cells by Epstein-Barr virus (EBV) may result in hemophagocytic syndrome (HPS) through enhanced cytokine secretion, particularly tumor necrosis factor-alpha (TNF-alpha), by EBV latent membrane protein-1 (LMP-1). One bewildering observation of HPS patients is relapsing disease or progression to T-cell lymphoma. This finding raises the question whether EBV LMP-1-expressing T cells may survive and proliferate in the cytokine milieu of HPS. To explore this possibility, we tested the sensitivity of LMP-1-expressing T cells to apoptosis in the presence of TNF-alpha. LMP-1 up-regulated TNF-alpha through TRAF2,5 and nuclear factor-kappaB pathway in T cells. The LMP-1-expressing T cells then became resistant to TNF-alpha-induced apoptosis. Interestingly, the expression of TNFR1 was remarkably down-regulated by LMP-1 in T cells. Furthermore, the TNF-alpha/TNFR1 downstream death signal TNFR1-associated death domain protein was constitutively recruited by LMP-1, and the activities of apoptotic caspases 3, 8, and 9 were suppressed. Reconstitution of TNFR1 successfully reversed the TNF-alpha-induced apoptotic cascades. Therefore, EBV LMP-1 not only activates T cells to proliferate but also confers resistance to TNF-alpha-mediated apoptosis via down-regulation of TNFR1 in the cytokine milieu of HPS. This finding provides a potential mechanism to explain the disease persistence or progression to T-cell lymphoma in HPS patients.