Hyperkalemia in patients with renal failure is frequently treated with a cation exchange resin (sodium polystyrene sulfonate, hereafter referred to as resin) in combination with a cathartic, but the effect of such therapy on serum potassium concentration has not been established. This study evaluates the effect of four single-dose resin-cathartic regimens and placebo on 5 different test days in six patients with chronic renal failure. Dietary intake was controlled. Fecal potassium output and serum potassium concentration were measured for 12 h. Phenolphthalein alone caused an average fecal potassium output of 54 mEq. The addition of resin caused an increase in insoluble potassium output but a decrease in soluble potassium output; therefore, there was no significant effect of resin on total potassium output. Sorbitol plus resin caused less potassium output than phenolphthalein plus resin. On placebo therapy, the average serum potassium concentration increased slightly (0.4 mEq/L) during the 12-h experiment. This rise was apparently abrogated by some of the regimens that included resin; this may have been due in part to extracellular volume expansion caused by absorption of sodium released from resin. Phenolphthalein regimens were associated with a slight rise in serum potassium concentrations (similar to placebo); this may have been due to extracellular volume contraction produced by high volume and sodium-rich diarrhea and acidosis secondary to bicarbonate losses. None of the regimens reduced serum potassium concentrations, compared with baseline levels. Because single-dose resin-cathartic therapy produces no or only trivial reductions in serum potassium concentration, and because this therapy is unpleasant and occasionally is associated with serious complications, this study questions the wisdom of its use in the management of acute hyperkalemic episodes.