This study was undertaken to define the hemodynamic changes in hypertension of chronic end-stage renal disease. Mean cardiac index in 75 uremic patients was higher (P< 0.001) than that of 42 normal volunteers while stroke index was not different from normals. The higher cardiac indices of uremic patients were accounted for by increased heart rates. Despite the significantly higher blood pressure in the uremics, their mean total peripheral resistance index was not different from that of normals.The total group of 75 patients included 52 hypertensive and 23 normotensive uremics. Cardiac index, heart rate, and stroke index were the same in 52 hypertensive and 23 normotensive uremics while mean total peripheral resistance index of hypertensive uremics was higher (P< 0.001) than normotensive uremics. Therefore, the hypertension in end-stage renal disease is sustained by a high total peripheral resistance.Bilateral nephrectomy in 12 hypertensive uremics resulted in no changes in cardiac index; a consistent decrease in blood pressure (P< 0.001) and a decrease in total peripheral resistance index (P< 0.001) occurred. Bilateral nephrectomy in eight additional uremics with malignant hypertension resulted in an actual increase in cardiac index (P< 0.001) with a consistent reduction in blood pressures (P< 0.001) and an even more dramatic decrease in total peripheral resistance (P< 0.001).These findings imply that a vasopressor substance of renal origin increasing peripheral resistance is the major factor in the pathophysiology of renal hypertension in the late stage of its natural history.