The mathematics used for urea kinetic modeling are currently based on a single-pool distribution of urea throughout the body. In this study, we evaluated which one of a single- or a two-pool model would be more appropriate for the prediction of directly measured urea decay during hemodialysis. A numerical method was used which minimizes the relative root mean square (RMS) error between a calculated single- or two-pool urea decay curve and the measured intradialysis decay in 13 equilibrated dialysis patients. Using a two-pool model, the RMS error was markedly lower (1.27 +/- 0.72%) than the values obtained with a single-pool model, either based on multiple urea concentrations (RMS error 3.14 +/- 1.36%; p < 0.01 vs. two-pool model) or only on pre- and postdialysis urea (RMS error 5.00 +/- 2.38%; p < 0.001). This resulted for the single-pool model in an overall underestimation of urea generation, distribution volume (V) and protein catabolic rate and in an overestimation of Kt/V versus the two-pool model. In individual cases, the difference reached up to 18.7%. Comparison of V calculated from the two-pool model versus V values determined from anthropometric formulae (Watson) resulted in similar mean values (34.05 +/- 4.87 vs. 33.09 +/- 4.19 liters; p = NS), with a weak correlation (n = 13, r = 0.75, p = 0.003). Individual values, however, again differed by up to more than 20%. In conclusion, the use of single-pool kinetic models, as well as of anthropometric estimations of V, should be regarded with care, especially when individual patients are considered instead of groups. The two-pool model follows the directly measured urea decay more exactly which results in substantial differences in calculated kinetic parameters.