We have found that human erythrocyte ghosts in 10 mM HEPES (pH 7.0) at 0 degrees C would crenate when 20-50 mM of Na+ or K+, 0.2-0.5 mM OF Ca++, Ba++, Sr++, or Mg++, or 10 muM of La+++ was added. The shape change after cation addition was faster than fixation by 1% glutaraldehyde at 4 degrees C and was readily reversible upon dilution of the cation. After incubation of ghosts in 10 mM HEPES (pH 7.0) at 37 degrees for 10-20 min there was a significant inhibition of subsequent crenation by cations. In a process that is believed to occur by a similar mechanism, whole red blood cells were observed to cup (invaginate) when 20 mM of a divalent or 0.1 mM of a trivalent cation was added. After neuraminidase treatment to remove the sialic acid charge groups, these same shape changes were observed in ghosts and whole cells. Another type of cation-induced crenation was found to follow upon the addition to whole cells of A23187 and Ca++ or Ba++ but not Mg++. This process is much slower than crenation in the ghost and is believed to be caused by a different mechanism.