The metabolism of (75)Se-labeled SeO(3) (2-) and its conversion by intact rat erythrocytes in vitro to a form which complexes with Cd and plasma proteins were studied. By utilizing both excess SeO(3) (2-) and N-ethylmaleimide to lower erythrocyte reduced glutathione (GSH) concentrations, it was shown that the uptake and metabolism of SeO(3) (2-) were GSH-dependent, the probable intermediate being glutathione selenotrisulfide (GSSeSG). Secondary release of selenium by rat erythrocytes had no relation to the erythrocyte transport of oxidized glutathione (GSSG). While fluoride depressed and chromate increased GSSG transport, chromate, a glutathione reductase inhibitor, decreased selenium release. This release appeared to be secondary to a reaction catalyzed by glutathione reductase. The similarity of I(50) values for chromate's inhibition of glutathione reductase and for the inhibition of selenium release further suggested a relationship between these two events. H(2)Se or a similar product of GSSeSG reduction is proposed to be the active product of SeO(3) (2-) metabolism by rat erythrocytes. By use of gel-filtration and ion-exchange methods it was noted that the incubation of H(2)Se with cadmium and plasma produced a Cd-Se complex indistinguishable from that produced by incubation of Cd, SeO(3) (2-), plasma, and erythrocytes in vitro, or that noted following the administration of Cd and SeO(3)in vivo. A mechanism whereby the tissue distribution and toxicity of cadmium are altered by selenium is suggested.