While the use of long-term antiretroviral therapy (ART) has improved immune function and reduced the incidence of some malignancies in human immunodeficiency virus (HIV-1) infected patients, this is not the case for non-Hodgkin’s lymphoma, an AIDS-defining cancer, and Hodgkin lymphoma, a non-AIDS defining cancer. Epstein-Barr virus (EBV) is an independent factor that adversely affects risk and/or survival among patients with Diffuse Large B cell Lymphoma (DLBCL) or classical Hodgkin lymphoma in immunocompetent patients as well as in HIV-1 infected individuals on ART. While cells infected with EBV in EBV-associated malignancies generally express one type of the latency programs, a small number of cells in these tumors are expressing EBV genes associated with lytic replication of the virus, which suggests that products from lytic or abortive-lytic replication may contribute to lymphomagenesis. However, the potential roles of these proteins in lymphomagenesis remain unclear. In this study we demonstrate that the EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase), an early protein produced during abortive/lytic EBV replication, is expressed in nasopharyngeal carcinoma (NPC) tumors in a mouse model of NPC, an EBV associated malignancy. Furthermore, screening of sera from 4 cohorts of patients diagnosed with AIDS, DLBCL, NPC and breast cancer (BC) by ELISA revealed an increase in IgG antibodies to the EBV-dUTPase in a subset of patients with AIDS, DLBCL and NPC relative to the controls. Finally, using an in vitro model of EBV infection we demonstrate that the EBV-dUTPase also inhibits T-cell function thus, allowing the proliferation of EBV immortalized B-cells. Altogether, our data support the premise that the EBV-dUTPase can modulate host immune responses and potentially alter the tumor microenvironment by promoting the survival/proliferation of immortalized B-cells, which may lead to lymphomagenesis. Key Words: Epstein-Barr virus, dUTPase, lymphomagenesis