The effect of ferric ammonium citrate (FAC) and desferrioxamine (DFO) on membrane iron and transferrin uptake have been investigated using SK-MEL-28 human melanoma cells which express the membrane-bound transferrin homologue, melanotransferrin, at high concentrations. Exposure of melanoma cells to DFO increased membrane non-Tf-bound Fe uptake (putative melanotransferrin Fe-binding sites), suggesting upregulation of the membrane Fe-binding component. However, exposure to FAC did not result in down-regulation. Indeed, an increase in non-Tf-bound membrane Fe was apparent. Results suggested that non-Tf-bound membrane Fe uptake occurred by two processes corresponding to the specific and non-specific mechanisms of Fe uptake from Tf described previously (Richardson, D.R. and Baker, E. (1990) Biochim. Biophys. Acta 1053, 1-12).