The objective of the present investigation was to determine to what extent polyamine uptake from the host contributes to the ability of tumor cells in overcoming the antiproliferative effect of a polyamine synthesis inhibitor. A mutant L1210 leukemia cell line deficient in polyamine transport was isolated by selection for resistance to methylglyoxal bis(guanylhydrazone), an extremely cytotoxic agent which is taken up by the same transport system as the polyamines. C57BL/6 x DBA/2 F1 mice inoculated with mutant L1210 cells survived on the average 60 to 70% longer than mice inoculated with the parental cells. The therapeutic effect of a polyamine synthesis inhibitor, DL-2-difluoromethylornithine (3% in the drinking water), was much greater on mice bearing mutant L1210 cells (87% increase in median survival time; 13 of 40 mice cured) than on mice inoculated with parental cells (22% increase in median survival time). Similar results, although not as striking, were obtained using athymic nude mice, indicating that the therapeutic difference is not merely due to increased immunogenicity of the mutant cells.