As reported by Jenkinson et al. (J Nutr 1982) and Prohaska et al. (J Nutr Biochem 1992) Cu deficiency (CuD) decreases the activity and mRNA expression of the selenoprotein GPx. Because both Se and Cu are important in oxidative defense, we wanted to determine the effect of a combined deficiency on the methionine (Met) sulfoxide reductase system, which is comprised of MsrA and MsrB. MsrA reduces L‐methionine S‐sulfoxide to Met and MsrB (a selenoprotein) reduces L‐methionine R‐sulfoxide to Met. In a 2 x 2 experiment, male weanling Sprague‐Dawley rats were fed an amino acid‐based diet containing 0 or 0.2 µg Se (as selenite)/g and <1 or 6 µg Cu (as Cu carbonate)/g for 5 wk. Neither Se nor Cu had an effect on MsrA enzyme activity or mRNA expression. Se and Cu interacted to affect MsrB enzyme activity; both Se deficiency and CuD decreased the activity, however, the decrease by CuD was only significant in rats fed 0.2 µg Se. CuD resulted in downregulation of MsrB mRNA. CuD decreased GPx in Se adequate rats. The results show that Cu has a role in regulation of selenoproteins; whether this role is direct or indirect is not known.1Pooled SD. 2nmol/min/mg protein, N=4/group. 3fold change, N=7‐9/group. 4SD for delta Ct. 5U/mg protein, N=7‐8/group.