Background: A significant proportion of patients admitted for acute decompensated heart failure (ADHF) that undergo volume reduction therapy are discharged with unchanged or increased bodyweight suggesting that the endpoints for these therapies are not optimally defined. We aimed to identify vectors that can help monitor changes in intravascular fluid volume, that in turn may more accurately guide volume reduction therapy. Methods: Data from six different impedance vectors and corresponding changes in intravascular volume derived from changes in hematocrit were obtained from 132 clinical congestion events in 56 unique patients enrolled in a multisite trial of early detection of clinical congestion events (DEFEAT PE). Mixed effects regression models were used to determine the relation between changes in impedance derived from six different vectors and changes in intravascular plasma volume. Results: Changes in impedance were negatively associated with changes in plasma volume. Two vectors, the right atrial ring to left ventricular ring and the left ventricular ring to the right ventricular ring, were most closely associated with changes in intravascular plasma volume. Conclusion: Impedance vectors derived from a multivector monitoring system reflect changes in intravascular plasma volume. Two of these vectors most closely track changes in plasma volume and may be used to more accurately guide and optimize volume reduction therapy.