The objective of the present investigation was to establish whether a known lymphoreticular-stimulating agent Corynebacterium parvum would augment the established antitumor activity of alpha-difluoromethylornithine in vivo. Furthermore, since C. parvum is known to boost cell mediated cytotoxicity, the effect of DFMO (DL-alpha-difluoromethylornithine X HCl X H2O) treatment was evaluated on macrophage and natural killer (NK) cell tumoricidal activity. DFMO administered alone, 1% or 2% in drinking water, inhibited 49.4% or 88.0% of B16 melanoma growth in vivo, respectively. Administration of C. parvum alone, three doses of 300 micrograms each, inhibited tumor growth 57.4%. When administered together, DFMO and C. parvum treatment resulted in 89.8% (1% DFMO) or 97.4% (2% DFMO) inhibition of melanoma growth depending upon the dose of DFMO. C. parvum-treated animals had increased levels of macrophage-mediated tumoricidal activity directed against B16 melanoma cells in vitro, however, NK cell activity was reduced. DFMO treatment alone had no effect on macrophage or NK cell tumoricidal activity. In animals receiving both C. parvum and DFMO treatments macrophage-mediated tumoricidal activity was augmented. These results demonstrate that C. parvum can augment the antitumor activity of DFMO in vivo, possibly through macrophage activation. Furthermore, in contrast to many other cancer chemotherapeutic drugs, DFMO is apparently not immunosuppressive regarding tumoricidal effector cells.