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The effect of xipamide on the intracellular concentration and transmembrane fluxes of Na+ and K+ was studied in 12 normal male subjects, using a double-blind cross-over design. After a run-in period on placebo for 1 week, the subjects were treated with either placebo (n=6) or xipamide 20 mg once a day (n=6) for 16 weeks and were then switched to the alternative medication for another 16 weeks. The intra-erythrocyte and intra-leucocyte Na+ concentration was increased by 11 and 7%, respectively, during xipamide administration, while the intracellular K+ concentration was decreased by 3 and 4%, respectively. No significant effect of xipamide could however be demonstrated on the ouabain-sensitive, bumetanide-sensitive or ouabain-bumetanide-resistaht 86Rb uptake and on the maximal 3H-ouabain binding in erythrocytes and leucocytes. The red cell Na+-Li+ countertransport was also not changed in the xipamide-treated subjects. Our data suggest that the increased intracellular Na+ concentration and the decreased K+ concentration in red and white blood cells of xipamide-treated subjects cannot be attributed to changes in the activity of the Na+ pump, the Na+-K+ cotransport or Na+-Li+ countertransport system or to changes in the number of active Na+ pump units.