The relationship between various transmembrane erythrocyte cationic fluxes and erythrocyte membrane and plasma lipids was examined in 53 healthy men. In single regression analysis, the erythrocyte Na+,Li(+)-countertransport and Na+,K(+)-cotransport activity was negatively related to the erythrocyte membrane cholesterol, phospholipids, and free fatty acids content. The Na+,K(+)-ATPase pump activity as assessed by the ouabain-sensitive Na+ efflux was also inversely related to the membrane cholesterol and phospholipids content. In multiple regression analysis, the red blood cell Na+,Li(+)-countertransport activity was independently and negatively related to membrane cholesterol and free fatty acids content. Data show that an elevated level of erythrocyte membrane lipids in healthy men is accompanied by a lower Na+,Li(+)-countertransport, Na+,K(+)-cotransport, and Na+,K(+)-ATPase pump activity.