Abstract The mechanism of the protective effect of Ca 2+ on cellular K + content was studied by examination of the effect of Ca 2+ on efflux of the K + analog, 86Rb +, from preloaded cells with the use of compounds which interfere with monovalent cation movements. Ca 2+ decreased 86Rb + efflux to the same extent in the presence and absence of ouabain, suggesting that Ca 2+ did not alter the activity of the (Na + + K +)-adenosine triphosphatase pump. Ca 2+ exerted a similar protective effect in the presence of furosemide, an inhibitor of K +-K + exchange, indicative that Ca 2+ was not inhibiting this pathway. Since Ca 2+ did not influence these pathways, it is concluded that Ca 2+ exerts its primary effect by slowing passive diffusion. In support of this, Ca 2+ also slowed 22Na + efflux. In addition, ethanol-induced leakage of 86Rb + was reversed by extracellular Ca 2+, suggestive of a Ca 2+-membrane phospholipid interaction.