We have previously reported that treatment of uremia by hypertonic hemodiafiltration (H-HDF) results in a more stable hemodynamic response as compared to standard hemodialysis (HD). The purpose of this study was to determine if plasma volume (PV) preservation was a significant factor in this response. Nine patients were studied during single treatment sessions of H-HDF and HD. Both sessions were 3 h in duration and the ultrafiltration rate and volume were matched. 10 μCi of 125I human serum albumin were injected 40 min before each session for measurement of PV. Changes in PV during the session were determined from the change in plasma albumin concentration and the hematocrit. The decrease in PV was significantly less during H-HDF. This was associated with a significantly higher plasma sodium and osmolality. The calculated effective osmolality during H-HDF was not only higher than in HD, but showed a significant increase at 2 and 3 h when compared to the baseline level (p < 0.05). The calculated volume of extravascular mobilization was higher during H-HDF and is probably the mechanism of the PV preservation. In conclusion, this study demonstrates that PV is preserved during H-HDF better than during HD as a result of a more adequate plasma refilling; this appears to be mediated by an increased plasma effective osmolality