The survival of implanted tumor cells in mice which had been treated with interferon in combination with either adriamycin or vincristine was evaluated. While the majority of tumor cells implanted into normal mice failed to survive (52.1 to 63.5%), most of those implanted into mice which had been pretreated with either adriamycin or vincristine survived. If the mice were secondarily treated with interferon, the ability of adriamycin or vincristine to inhibit the survival of implanted tumor cells was restored within 24 hours. Restoration of tumoricidal activity by interferon treatment was more evident in the adriamycin pretreated mice. Peritoneal macrophages isolated from mice pretreated with both interferon and adriamycin had an increased tumoricidal activity, when compared with those isolated from mice treated with adriamycin alone. This interferon dependent enhancement of tumoricidal activity was comparable with that obtained by treating mice with lymphokines a product of Con A treated lymphocytes isolated from BCG treated mice. These results suggested that both adriamycin and vincristine may damage the macrophages required for the natural host defense mechanism and allow the implanted tumor cells to survive. Interferon may, however, protect the macrophages from drug induced damage.