Natural interferons (nIFNs) -alpha and -gamma were used to treat nude mice bearing bilateral xenografts of human breast cancer cells (MCF-7 and BT 20). The IFNs were administered singly or in combination by means of intralesional (i.l.) or intraperitoneal (i.p.) injections. In the animals treated intralesionally 1 of the 2 tumors was injected to study the local therapeutic effects, while the contralateral one was left undisturbed and used to assess systemic effects. Treatment of MCF-7 tumors with i.l. injections of nIFN-alpha and nIFN-gamma combined resulted in complete regression of the injected tumors in 8 of 20 mice treated for 2 weeks and in 10 of 10 mice of an additional group treated for 4 weeks. The corresponding contralateral tumors showed complete regression in 2 mice treated for 4 weeks and partial responses in the others. Incomplete responses were also observed when the IFNs were used singly or when they were delivered intraperitoneally. Similarly, in BT 20 xenografts the best results were obtained with i.l. injections of the 2 IFNs combined, but no complete regressions were achieved. These experiments provide further evidence for a synergistic interaction of nIFN-alpha and nIFN-gamma in vivo and indicate that the potentiated antitumoral activity is greater when these interferons are administered i.l.