The effect of acute and short-term administration of ketanserin on the intracellular concentration and transmembrane fluxes of sodium and potassium in erythrocytes was studied in 12 sodium-replete, normal male subjects. The subjects received 40 mg ketanserin three times a day for one week. Blood samples were drawn before and 2.5 hours after the first dose, 12 hours after the evening dose of the sixth day and 1.5 hours after the morning dose of the seventh day. The intra-erythrocyte sodium concentration was not changed following the first dose of ketanserin, but was decreased (p less than 0.05) during short-term treatment with ketanserin. The ouabain-sensitive 86Rb-uptake, an estimate of the Na+,K+-ATPase pump activity, was decreased (p less than 0.001) after acute ketanserin administration, but not (p = 0.07) during short-term treatment. This change in intra-erythrocyte sodium concentration was related (r = 0.73, p less than 0.01) to the change in ouabain-sensitive 86Rb-uptake. The red cell Na+,K+-cotransport and Na+,Li+-countertransport activity were not changed during acute and short-term administration of ketanserin. The results indicate that short-term ketanserin administration decreases the intra-erythrocyte sodium concentration, but the flux measurements cannot explain this observation.