Among chronic hemodialysis patients, 217 hospitalizations per 1000 patient-years are attributed to congestive heart failure; some are attributable to unrecognized hypervolemia. Hypervolemia can be detected by relative plasma volume (RPV) monitoring. The purpose of this study was to examine among 308 patients on long-term hemodialysis the value of slope of RPV compared with either ultrafiltration (UF) volume or UF rate index in determining all-cause mortality. RPV slopes were calculated by least-squares regression. These slopes were related to all-cause mortality in unadjusted and adjusted Cox proportional hazards models. Over a median follow-up of 30 months (interquartile range: 14 to 54 months) 96 patients (31%) died, yielding a crude mortality rate of 113/1000 patient-years. We found the following: (1) RPV slope measurements were of prognostic significance (hazard ratio of flatter slopes [>1.39%/h]: 1.72; P=0.01); (2) the UF volume alone was not prognostically informative (hazard ratio of higher UF volume [>2.7 L of dialysis]: 0.78; P=0.23); (3) the UF rate index alone was also not prognostically informative (hazard ratio of higher UF rate index [>8.4 mL/kg per hour]: 0.89; P=0.6); and (4) the prognostic relationship of RPV slope to mortality was independent of conventional and unconventional cardiovascular risk factors including the UF volume, UF rate, or UF volume per kilogram of postweight. RPV monitoring yields information that is prognostically important and independent of several risk factors including UF volume, aggressiveness of UF, and interdialytic ambulatory blood pressure. Its use to assess excess volume-related morbidity among chronic hemodialysis patients should be tested in randomized, controlled trials.