High red blood cell (RBC) spermidine levels have been observed in patients harboring various histological types of cancer. In an attempt to explain the mechanism of RBC spermidine uptake in the malignant cell growth process, erythrocytes from normal and (3LL) Lewis lung carcinoma grafted mice were incubated with [14C] spermidine in the presence of PBS or plasma from normal or 3LL grafted mice. Though RBC of cancer mice harbor abnormally elevated spermidine concentrations as compared with those of controls, when incubated with PBS, 3LL grafted mice exhibit [14C] spermidine uptake three times higher than that of normal mice erythrocytes in the same incubating conditions. Moreover, if plasma incubations always increase spermidine uptake in RBC from cancer mice compared with erythrocytes only incubated with PBS, plasma incubations are responsible for two opposite effects in RBC of normal mice: plasma increases spermidine uptake in PBS unwashed erythrocytes and lowers it in PBS washed RBC. One possible explanation for the observed plasma stimulating effect in RBC spermidine uptake might be the presence of a plasma component common to plasma from normal and cancer mice, able to interact with RBC membrane proteins. In erythrocytes from cancer mice, the high spermidine concentration would be responsible for the observed compactness in band 3 proteins involved in ionic transport through RBC stroma. In normal mice erythrocytes which exhibit low polyamine levels, the observed dissociation of band 3 proteins might explain the spermidine uptake in PBS washed normal RBC incubated with plasma. In vivo, this plasma component would participate in the stabilization of normal mice membrane proteins involved in RBC spermidine uptake.