Male weaning rats were pair-fed a low-zinc diet or a control diet. After 10 d, the animals fed the low-zinc diet showed physiologic signs of deficiency; however, they showed no clinical symptoms. Their estimated whole body zinc was 25-mu-mol versus 39-mu-mol for the controls. The Zn-65 absorption increased 2-fold and the tissue distribution altered: muscle and erythrocytes contained more, small intestine and liver less activity at 0.5 h postdose. In vitro, the erythrocyte Zn-65 uptake rate increased also. The Zn-65 uptake experiments required small quantities of erythrocytes. The difference observed between the deficient and control cells was significant and showed little overlap. The increase of the Zn-65 uptake from a medium was not affected when the animals underwent endotoxin exposure 24 h before, as was reported to occur in whole blood Zn-65 uptake. Therefore, we suggest the in vitro erythrocyte Zn-65 uptake, performed in a standardized, near physiologic medium, to detect early, subclinical zinc deficiency.