Cu and Zn have naturally occurring non radioactive isotopes, and their isotopic systematics in a biological context are poorly understood. In this study we used double focussing mass spectroscopy to determine the ratios for these isotopes for the first time in mouse brain. The Cu and Zn isotope ratios for four strains of wild-type mice showed no significant difference (delta 65Cu -0.12 to -0.78 permil; delta 66Zn -0.23 to -0.48 permil). We also looked at how altering the expression of a single copper binding protein, the prion protein (PrP), alters the isotope ratios. Both knockout and overexpression of PrP had no significant effect on the ratio of Cu isotopes. Mice brains expressing mutant PrP lacking the known metal binding domain have delta 65Cu isotope values of on average 0.57 permil higher than wild-type mouse brains. This implies that loss of the copper binding domain of PrP increases the level of 65Cu in the brain. delta 66Zn isotope values of the transgenic mouse brains are enriched for 66Zn to the wild-type mouse brains. Here we show for the first time that the expression of a single protein can alter the partitioning of metal isotopes in mouse brains. The results imply that the expression of the prion protein can alter cellular Cu isotope content.