BACKGROUND Volume overload is a factor in the hypertension of hemodialysis (HD) patients. Fluid removal is therefore integral to the hemodialysis treatment. Fluid removal by hemodialysis ultrafiltration (UF) may cause intradialytic hypotension and leg cramps. Understanding blood pressure (BP) and volume changes during UF may eliminate intradialytic hypotension and cramps. Studies (S1, S2, and S3) were carried out to determine the amount and direction of changes in body fluid compartments following UF and to determine the relationships between BP, changes in blood volume (DeltaBV), central blood volume (CBV), cardiac output (CO), peripheral vascular resistance (PVR) plus total body water (TBW), and intra- and extracellular fluid volumes (ICF, ECF) in both the whole body and body segments (arms, legs, trunk). METHODS Indicator dilution technology (Transonic) was used for CBV, CO, and PVR; hematocrit monitoring (Crit-Line) was used for DeltaBV segmental bioimpedance (Xitron) for TBW, ICF, and ECF. RESULTS S1 (n = 21) showed UF sufficient to cause DeltaBV of -7% and lead to minor changes (same direction) in CBV and CO, and with cessation of UF, vascular refilling was preferential to CBV. S2 (n = 20) showed that predialysis HD patients are ECF-expanded (ECF/ICF ratio = 0.96, controls = 0.74 [P < 0.0001]) and BP correlates with ECF (r = 0.47, P = 0.35). UF to cause DeltaBV of -7% was associated with a decrease in ECF (P < 0.0001) and BP directly (r = 0.46, P = 0.04) plus DeltaBV indirectly (r = -0.5, P = 0.024) correlated with PVR, while CBV and CO were maintained. S3 (n = 11) showed that following UF, total-body ECF changes were correlated with leg ECF (r = 0.94) and arm ECF (r = 0.72) but not trunk ECF. Absolute ECF reduction was greatest from the legs. CONCLUSIONS Predialysis ECF influences BP and UF reduces DeltaBV and ECF, but CBV and BP are conserved by increasing PVR. ECF reduction is mainly from the legs, hence may cause cramps. Intradialytic hypotension is caused by failure of PVR response.