Among hemodialysis patients the assessment of dry-weight remains a matter of clinical judgment because tests to assess dry-weight have not been validated. The objective of this study was to evaluate and validate relative plasma volume monitoring as a marker of dry-weight. We performed relative plasma volume monitoring using the Critline monitor at baseline and 8 weeks in 150 patients participating in the dry-weight reduction in hypertensive hemodialysis patients (DRIP) trial. The intervention group of 100 patients had dry-weight probed whereas 50 patients served as time controls. Relative plasma volume slopes were defined as flat when they were less than the median (1.33%/hour) at the baseline visit. Among predominantly (87%) African-American hemodialysis patients, we found that flat relative plasma volume slopes suggest a volume overloaded state because of the following reasons: 1) probing dry-weight in these patients leads to steeper slopes; 2) those with flatter slopes at baseline had greater weight loss; 3) both baseline relative plasma volume slopes and the intensity of weight loss were found to be important for subsequent change in relative plasma volume slopes; and most importantly 4) relative plasma volume slopes predicted the subsequent reduction in interdialytic ambulatory systolic BP. Those with the flattest slopes had the greatest decline in BP upon probing dry-weight. Both baseline relative plasma volume slopes and the change in relative plasma volume slopes were important for subsequent changes in ambulatory systolic BP. We conclude that relative plasma volume slope monitoring is a valid method to assess dry-weight among hypertensive hemodialysis patients.