The noninvasive external radioflux detection method (ERD) measures net transvascular flux of tracer protein into and out of the lung extravascular compartment (EV) and time to zero flux between compartments. With this information we can now estimate regional interstitial volume in the field of the external probe (VIs). Dividing the mass of EV tracer by VIs, we obtain interstitial concentration ([Is]). Directly sampling plasma concentration of the tracer, we can construct plasma-interstitium equilibration curves that are analogous to plasma-lymph equilibration curves without invasive surgery. We completed 46 ERD studies in 21 sheep with chronic lung lymph fistulas. Sheep were studied under baseline conditions (n = 30) and after elevating left atrial pressure by mitral obstruction (n = 7), or intravascular volume infusion (n = 8), and increasing lung vascular permeability (n = 1). In each study we compared the slope of the regression through plasma-lymph concentration of tracer protein over time ([P]-[L], measured directly) with that through values of plasma-interstitial concentration ([P]-[Is], assessed noninvasively), an index of vascular permeability. For this correlation, r = 0.94, and the regression line approximates identity. Mean [Is] appears to approximate [L] in sheep.