In 26 patients, a linear relationship between ΔKt/V (equilibrated minus single pool) and dialysis efficiency K/V was noted (r = −0.72). To determine if such a relationship would be supported by formal urea kinetic analysis, t, Kd, and V were randomly varied in 1,400 simulations using both intracellular/extracellular and regional blood flow 2 pool variable volume models. In the intracellular/extracellular model, ΔKt/V was best correlated with Kd/Kc (r = −0.96), where Kc is the intercompartmental clearance. Kc was not correlated with V, which translated into a lack of correlation between ΔKt/V and V, and a better correlation between ΔKt/V and Kd than between ΔKt/V and K/V. In the regional blood flow model ΔKt/V was best correlated with Kd/QL (r = −0.99), where QL is the perfusion of the low flow compartment. QL was correlated with V because QL is a function of cardiac output, which varies with surface area and therefore with V. In the regional blood flow model, ΔKt/V did correlate with V (r = 0.49), and better with K/V (r = −0.76) than with K (r = −0.47), similar to the results in patients. The slope of ΔKt/V on K/V depended upon fQL (the fractional perfusion of the low flow compartment) and on cardiac index. At an fQL of 0.15 and a cardiac index of 2.85, the theoretical slope was similar to that seen in observational data: ΔKt/V = −0.6 × K/V + 0.03. The results show that the regional blood flow model predicts the observed relation between ΔKt/V and K/V, whereas the intracellular/extracellular model fails in this task unless one arbitrarily ties Kc to V.