Inadequate plasma refilling is an important determinant of vascular instability during hemodialysis. Hypotension is more frequent toward the end of dialysis, as the patient reaches dry weight. This study compared plasma volume changes in 12 patients dialyzed with constant ultrafiltration and a constant dialysate Na of 140 mEq/L (Group A), sequentially decreasing ultrafiltration (50% in first hour, 30% in the second hour, and 20% in the third hour) using constant dialysate Na (Group B), and sequentially decreasing ultrafiltration with sequentially decreasing dialysate Na from 150 to 140 mEq/L (Group C). All of the patients had midweek dialysis with each protocol. Blood pressure, hematocrit, blood urea nitrogen, serum osmolality, and albumin were determined before and hourly thereafter. Ultrafiltration was constant at 12.2 ml/min in Group A but 18.4 ml/min in the first hour, 11.0 in the second hour, and 7.3 in the third hour in Groups B and C. In Group A, plasma volume did not change during the first hour but decreased in the second and third hours (4.9%). In Group B, plasma volume decreased during the first and second hours 5.6% but slightly increased during the third hour 5.3%, whereas in Group C, plasma volume increased during the first hour (2.1%), was unchanged during the second hour, and decreased 1.2% during the third hour. These data suggest that plasma refilling is enhanced during hemodialysis using sequentially decreasing ultrafiltration and high-to-low dialysate Na (Group C); this strategy may be preferred to hemodialysis with constant dialysate Na and ultrafiltration (Group A) or sequentially decreasing ultrafiltration with constant dialysate Na (Group B) when improvement in vascular stability is needed.