We have quantified the effect of EGTA on K exodus and uptake in human blood lymphocytes. When lymphocytes were exposed to a medium containing an EGTA concentration that resulted in an ionized Calcium (Ca) of less than 10 microM, K exodus began to increase. This increase reached nearly threefold that of the control rate in a medium containing sufficient EGTA to reduce the ionized Ca concentration below 0.1 microM. When K exodus was increased, K uptake increased proportionately. This increase in K uptake represented active transport and was associated with an 80% increase in intracellular Na concentration from 15 to 27 mM. The addition of Ca to a medium containing EGTA reversed to normal the increased K exodus and uptake. Histidine, a potent chelator of divalent cations other than Ca, had no effect on K transport. These data indicate that extracellular Ca chelation leads to an increase in lymphocyte membrane permeability and cation leak. This increased leak is associated with an elevation of the cell Na and an increase in transport to a rate equivalent to that of the exodus rate. The compensatory increase in active transport maintains the cell monovalent cation concentration within 10 to 15 mM of unperturbed levels.