Dialysate sodium and ultrafiltration profiling are two methods to reduce symptoms during hemodialysis. The objective of the study was to determine the efficacy of combining these techniques to reduce symptoms in chronic hemodialysis patients. Blood volume changes were measured to determine whether any benefit of profiling could be explained through this mechanism. Patients were randomized to profiled dialysate sodium and ultrafiltration or constant dialysate sodium and ultrafiltration. The study was a two-period, two-treatment, crossover design with repeated measures. The primary outcome was hypotension and/or symptomatic events observed by the dialysis nurse. Secondary outcomes were symptom survey scores, weights, BP, and blood volume changes. Thirty-three patients were randomized. On standard treatment, 30.6% of dialysis sessions were symptomatic compared with 20.4% on profiled treatments. The odds ratio for development of hypotension or symptomatic event on profiled treatments was 0.61 (95% confidence interval, 0.39 to 0.96) compared with standard treatment. Patients had lower symptom scores by questionnaire in both the intradialytic and the interdialytic periods during profiled treatments. Predialysis weight was greater during profiled treatments by 0.3 kg (P = 0.008), but there were no differences in postdialysis weight, BP, or thirst. There was no difference in maximum decrease in blood volume during the two treatments (standard, -11.2%; profiled, -10.0%; P = 0.08), but there was a significant difference in the rate of change in blood volume (standard, -2.96%/h; profiled, -1.96%/h; P < 0.001). Decrease in blood volume, rate of change in blood volume, and predialysis weights were not associated with hypotension or symptomatic dialysis sessions. In conclusion, dialysate sodium and ultrafiltration profiling significantly reduces hemodialysis-related symptoms. Profiling reduces the slope of the blood volume curve during dialysis, but blood volume changes are not predictive of symptomatic events for an individual patient.