Intracellular Pb2+ ions can replace Ca2+ ions in stimulating the Ca-dependent K permeability of human red blood cells. In metabolically depleted resealed ghosts, the threshold for stimulation of 86Rb efflux by internal Pb2+ is around 5 X 10(-10) M, and stimulation is half-maximal at about 2 X 10(-9) M, and maximal at 10(-8) M Pb2+. There is no effect on 22Na efflux in this concentration range. 86Rb efflux is antagonized by internal Mg2+ ions, and by the channel-blocking drugs quinidine and diS-C2(5), as observed for the Ca-dependent K permeability in red cells. In ghosts containing EDTA, which prevents any internal effects of Pb2+ ions, external Pb2+ increases both 22Na and 86Rb permeability when its concentration exceeds 6 X 10(-7) M. This effect is seemingly unrelated to the Ca-dependent K permeability. This work makes extensive use of Pb2+ ion buffers, and gives information about their preparation and properties.