Based mainly on the simplicity of its calculation, the urea reduction ratio (URR) has been suggested as an alternative to urea kinetic modeling (Kt/V) as a measure of hemodialysis adequacy. However, recent studies have raised questions concerning the accuracy of URR, particularly in the presence of residual kidney function (KrU). This study was initiated to evaluate the relationship between URR and Kt/V under a variety of dialysis conditions. Equations based on the variable-volume, single-pool model described by Gotch were used to construct a model incorporating the variables used in the estimation of URR and Kt/V. The model’s prediction of URR correlated closely with measured URR in 30 patients (r = 0.9987, p < 0.000001). This analytic approach showed that changes in each of several dialysis parameters caused divergence in the values of URR and Kt/V. The model showed that URR could be less than 0.65, while total Kt/V was greater than 1.2, whether or not KrU was present. In fact, when KrU was greater than 1.0, URR could be less than 0.65, while Kt/V might be 2.0 or higher. On the other hand, the model showed instances where URR could be greater than 0.65, when Kt/V was less than 1.2. This occurred only when KrU was less than 1.0. To determine the prevalence of these anomalies in clinical practice, 767 kinetic modeling determinations were evaluated in 207 patients. One of the above discrepancies was observed at least once in 30.9% of the patients, representing 12.1% of all determinations. In addition, it was found that omitting KrU from the calculation of Kt/V generally leads to a Kt/V <1.2. This, when associated with a URR <0.65, could erroneously imply inadequate dialysis. The patient data are consistent with the view that URR and Kt/V are the net result of several variables that may act together or even in opposing directions. Based on this mathematical model and the observed clinical data, the use of URR alone to assess dialysis adequacy, or neglecting the contribution of KrU to Kt/V, may lead to changes in the dialysis prescription that are neither correct nor necessary.