The effect of ammonium chloride on the cellular Na+, K+ and water has been examined in human and horse (high K), cow (medium K) and cat (low K) red cells. It was found that high K red cells, especially those of the horse, gained water an Na+, whereas the net movement of K+ was negligible. There was a correlation between the increase of cellular Na+ concentration and of the packed red cell volume. In contrast, the packed cell volume of low K red cells increased slightly or not at all, and Na+ ions leaked out from the cells. The high K cells had a lower Cl concentration and higher buffer capacity than the low K cells. The results obtained with the medium K (cow) cells usually lay between those of the other two cell types. In all the cases both the plasma and cell pH decreased resulting from the addition of ammonium chloride. The mechanism of movements of water and Na+ ions in high K cells remained unsolved, but the response of low K cells to ammonium chloride was near that of a cation exchange resin.