alpha-Difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, has been shown to be growth inhibitory in a wide variety of normal and tumor cell systems. Since cells of the host defense system are among the most rapidly proliferating cells in the body, DFMO may inhibit certain components of this system. In order to assess this possibility, four randomized groups of C57BL/6 mice were maintained either on water throughout (controls) or on 2% DFMO in drinking water for various periods of time. Mice were given DFMO from Days -4 to 0, Days 0 to +4, or Day 0 to day of assay. On Day 0 randomly selected mice from each group received P815 tumor allografts. Daily from Days +3 to +14, pools of spleen cells from three mice per group were assessed for allospecific cytolytic T-lymphocyte, antibody formation, natural killer cell, and phagocytic cell activities. While natural killer cell and phagocytic cell activities remained essentially unchanged under all conditions, both cytotoxic T-lymphocyte and antibody responses were modified. Somewhat similar effects were seen with both responses and involved to varying degrees: (a) a delay of the initiation of rapid increase in the response but not in the onset of first detectable response; (b) delay in the time of peak response; (c) increased level of maximal response; (d) two peaks of maximal response. The data indicate that DFMO treatment of whole animals, dependent upon schedule of administration and time of assay, induces very selective effects on both cytotoxic T-lymphocyte and antibody responses, without apparent modification of nonspecific host defense mechanisms, with the overall effect being a prolongation of the period of specific response.