Routine assessment of dry weight in chronic hemodialysis patients relies primarily on clinical evaluation of patient fluid status. We evaluated whether measurement of postdialytic vascular refill could assist in the assessment of dry weight. Twenty-eight chronic, stable hemodialysis patients were studied during routine treatment sessions using constant dialysate temperature and dialysate sodium concentration, and relative changes in blood volume were monitored using Crit-Line III monitors throughout this study. The study was divided into three phases. Phase 1 studies evaluated the time-dependence of vascular compartment refill after completion of hemodialysis. Phase 2 studies evaluated the relationships in patient subgroups between intradialytic changes in blood volume and the presence of postdialytic vascular compartment refill during that last 10 minutes of hemodialysis after stopping ultrafiltration. Phase 3 studies evaluated the extent of dry weight changes following the application of a protocol for blood volume reduction, postdialytic vascular compartment refill, and correlation with clinical evidence of intradialytic hypovolemia and/or postdialytic fatigue. Phase 3 included anywhere from three to five treatments. Phase 1 studies demonstrated that despite interpatient variability in the magnitude of postdialytic vascular compartment refill, when significant refill was evident, it always continued for at least 30 minutes. However, the majority of refill took place within 10 minutes postdialysis. Phase 2 studies identified 3 groups of patients: those who exhibited intradialytic reductions in blood volume but not postdialytic vascular compartment refill (group 1), those who exhibited intradialytic reductions in blood volume and postdialytic vascular compartment refill (group 2), and those whose blood volume did not change substantially during hemodialysis treatment (group 3). In phase 3 studies, use of an ultrafiltration protocol for blood volume reduction and monitoring of postdialytic vascular compartment refill combined with clinical assessment of hypovolemia and postdialytic fatigue demonstrated that patients often had a clinical dry weight assessment which was too low or too high. In all 28 patients studied, dry weight was either increased or decreased following use of this protocol. Determination of the extent of both intradialytic decreases in blood volume and postdialytic vascular compartment refill, combined with clinical assessment of intradialytic hypovolemia and postdialytic fatigue, can help assess patient dry weight and optimize volume status while reducing dialysis associated morbidity. The number of hospital admissions due to fluid overload may be reduced.