The effects of intralesional injections of human natural and recombinant interferons-alpha (nIFN-alpha and rIFN-alpha A) were studied in nude mice bearing bilateral xenografts of human mammary carcinoma cells (BT 20, MCF-7). One tumor of each animal received intralesional injections, while the contralateral tumor was left undisturbed. Thus, the injected tumors were subjected to the local action of the IFNs whereas the opposite ones were exposed to the systemic effects of the IFNs seeping into the subcutaneous tissue following the intratumoral injection. When used singly these IFNs exerted an inhibitory effect on the growth of both injected and contralateral tumors, but failed to cause complete regression. Many of the cells of treated BT 20 xenografts showed significant morphological alterations (increased cell volume and nuclear pleomorphism) as compared to the untreated controls. Morphological alterations in MCF-7 tumors were difficult to assess because of the inherent pleomorphism of these cells. The immunoreactivity of BT 20 and MCF-7 tumors to monoclonal antibodies directed against milk fat globule proteins and against HLA antigens was not appreciably affected by treatment with these IFNs. This study confirms that intralesional injections of human IFNs-alpha partially inhibit the growth of human breast cancer xenografts, probably through a direct effect on the carcinoma cells. Under the present experimental conditions, the intralesional and the subcutaneous routes of administration appear to offer comparable antitumor effectiveness.