A genetic control of blood magnesium (Mg) levels has been suggested. To investigate the mechanisms and the biologic significance of this genetic regulation, a mouse model, ie, mice selected for low magnesium level (MGL) and high magnesium level (MGH), was developed. The purpose of this study was to explore the Mg status and Mg metabolism in female MGL and MGH mice. We observed that MGL mice had reduced total and ionized plasma Mg, lower erythrocyte Mg, lower tibia, and kidney Mg levels. In contrast, total urinary Mg and (25)Mg levels were significantly higher in MGL mice. MGL mice had smaller total Mg exchangeable pool masses compared with MGH, and fractional transport rates of Mg (exchange constant) were different. In vitro (25)Mg enrichments in erythrocytes from MGL mice were significantly lower. Moreover, Mg efflux from erythrocytes was significantly higher in MGL. In conclusion, this work demonstrates that MGL mice present lower body stores of Mg than MGH mice and lower body Mg retention. This is confirmed at a cellular level by a lower enrichment of (25)Mg in erythrocytes. The lower retention of Mg by MGL erythrocyte in comparison to MGH appears to be partly due to a higher Mg efflux in MGL erythrocyte. It can be hypothesized that a genetic factor that modulates Na(+)/Mg(2+) exchanger activity may be important in the regulation of Mg metabolism. Further investigations on the mechanisms responsible for differences in Mg retention between MGL and MGH mice could contribute to a better understanding of the genetic regulation of cellular Mg.