The oncoprotein Tax of human T-cell leukemia virus type I (HTLV-1) is the major mediator of viral pathogenesis in infected individuals. Expression of Tax under the regulation of the human granzyme B promoter in mice results in a lymphoproliferative disorder resembling adult T-cell leukemia/lymphoma (ATL). Tax expression is associated with the production of high levels interferon-γ (IFN-γ) in HTLV-1-infected CD4⁺ cells and Tax-transgenic tumors. We examined the role of IFN-γ in tumorigenesis, by mating Tax-transgenic mice with a gene-specific knockout for IFN-γ. IFN-γ^-/- Tax⁺-transgenic mice show accelerated tumor onset (median, 4 versus 6 months), dissemination (median, 5 versus 7 months), and death (median, 7 versus 10 months), compared with IFN-γ^+/- or IFN-γ^+/+ Tax⁺ mice. Pathologic and immunophenotypic characteristics of tumors from all genotypes are indistinguishable, except for enhanced interleukin 2 receptor-β (IL-2Rβ) and suppressed intercellular adhesion molecule-1 (ICAM-1) expression on tumors from IFN-γ^-/- Tax⁺ transgenic mice. IFN-γ^-/- tumors demonstrate enhanced CD31 (platelet-endothelial CAM-1 [PECAM-1]) staining compared with those from IFN-γ^+/- or IFN-γ^+/+ Tax⁺ mice. Angiogenesis-specific cDNA microarray analysis identified 4 mediators of angiogenic growth differentially expressed in tumors from Tax⁺IFN-γ^-/- mice compared with Tax⁺IFN-γ^+/+ littermates. As confirmed by reverse transcription-polymerase chain reaction (RT-PCR), loss of IFN-γ results in down-regulation of tumor necrosis factor-α (TNF-α) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) while up-regulating expression of vascular endothelial growth factor (VEGF) and tenascin C. These results provide insight into a possible mechanism by which IFN-γ contributes to host resistance against HTLV-induced tumors through an angiostatic effect. (Blood. 2004;104:3305-3311)