Expression of a dominant negative mutant IFNγR1 in murine SCK and K1735 tumor cells rendered them relatively unresponsive to IFNγ in vitro and more tumorigenic and less responsive to IL-12 therapy in vivo. IL-12 induced histologic evidence of ischemic damage only in IFNγ-responsive tumors, and in vivo Matrigel vascularization assays revealed that while IFNγ-responsive and -unresponsive tumor cells induced angiogenesis equally well, IL-12 and its downstream mediator IFNγ only inhibited angiogenesis induced by the responsive cells. IL-12 induced angiogenesis inhibitory activity in the responsive cells, which may be attributable to production of the chemokine IP-10. Thus, IL-12 and IFNγ inhibit tumor growth by inducing tumor cells to generate antiangiogenic activity.