Clinical and experimental data suggest that erythrocyte (RBC) polyamine (PA) levels are markers of tumor proliferation during total parenteral nutrition (TPN). The purpose of this experiment was to determine whether the inhibition of PA synthesis during TPN was greater in tumors than in normal host tissue. Rats bearing a subcutaneous fibrosarcoma were randomized to receive a chow diet (n = 5), TPN (n = 5), or TPN + difluoromethylornithine (DFMO) (an irreversible inhibitor of ornithine decarboxylase (ODC), at 1000 mg/kg body wt/day n = 4) for 6 days by continuous central venous infusion. TPN + DFMO resulted in a higher plasma albumin level and lower tumor ODC activity compared with chow feeding or TPN. Liver ODC activity was similar for the chow fed, TPN, and TPN + DFMO groups. RBC putrescine, tumor putrescine, and tumor spermidine levels were significantly lower in the TPN + DFMO group compared with the chow fed and TPN groups. RBC spermidine, RBC spermine, and tumor spermine levels were significantly increased with TPN + DFMO compared with TPN alone. DFMO did not produce diarrhea or weight loss. Increased RBC spermidine may indicate a toxic effect of DFMO on the tumor, resulting in leakage of tumor spermidine into the extracellular space. The data suggest that DFMO during TPN can selectively inhibit tumor PA synthesis and may improve host utilization of nutrients.