Nude mice bearing bilateral xenografts of human breast carcinoma cells (MCF-7 and BT20) were treated with 2 or 45-day cycles of intralesional (i.l.) injections of human natural interferon beta (nIFN-beta) alone or in combination with human natural interferon gamma (nIFN-gamma). The injections were administered to only 1 of the 2 tumors in each animal, thus making it possible to assess at the same time local therapeutic effects in the injected tumors and systemic effects in the contralateral ones. When n-IFN-beta was used as a single agent only mild local antitumor effects and virtually no systemic effects were observed. In contrast, the combined administration of nIFN-beta/nIFN-gamma produced marked antiproliferative effects, presumably as a result of the synergistic action of type I and type II IFNs. These effects ranged from complete regression documented histologically in 2 MCF-7 tumors to varying degrees of growth inhibition with persistence of residual microscopic or grossly detectable tumor. Local effects were more pronounced than systemic effects. The therapeutic efficacy of nIFN-beta proved to be greater than that of recombinant interferon beta (rIFN-beta). In MCF-7 tumors nIFN-beta appeared to be less effective than nIFN-alpha, whereas the opposite was true for BT20 tumors.