Background. Cardiac disease is the major cause of death in hemodialysis patients (HD). It is now clear that aldosterone has deleterious effects in the cardiovascular system. In the present study, we evaluated the effects of an aldosterone-antagonist, spironolactone, on the extrarenal regulation of potassium in HD patients. Furthermore, to validate the effectiveness of the spironolactone dose-design, we measured the expression of Na+-channel (ENaC alpha subunit) in peripheral blood mononuclear cells (PBMC), before and after a two-week course of spironolactone. Methods. The study design included a two-week baseline period, followed by spironolactone treatment (50 mg three times weekly for 15 days), and by a two-week washout period and then a two-week placebo period. An oral K+ load (0.3 mEq/K+ kg body weight plus carbohydrates) was administered at the end of each period, and time-course of plasma potassium was evaluated. ENaC expression in PBMC was assessed before and after spironolactone. Results. The maximal increase in plasma potassium after the K+ carbohydrate load was: control 5.33 ± 0.88 mEq K+/L; spironolactone 5.23 ± 0.68 mEq K+/L; placebo 5.38 ± 0.61 mEq K+/L (N = 9). No patients developed hyperkalemia during the spironolactone treatment period. ENaC expression was significantly higher in all six HD patients studied, compared to control subjects (P < 0.05). Treatment with spironolactone in HD patients reduced alpha subunit mRNA expression to values similar to those of normal subjects. Conclusion. Spironolactone may be considered for the treatment of selected chronic HD patients. The effect of the drug on a known target of aldosterone, the ENaC, demonstrates the effectiveness of the drug to block aldosterone effects in nonepithelial tissues.