To investigate an appropriate solute kinetics model for clinical application, we analyzed urea nitrogen (UN) and creatinine (Cr) kinetics by a variable-volume two-compartmental model (2CM) and a regional blood flow model (RBF) in 44 hemodialysis patients with varying proportions of first compartmental volume and regional volume (p<sub>1</sub>). Solute kinetics could not be solved in some of the patients with higher p<sub>1</sub> values, and there were more solution failures by the RBF than by the 2CM. The solute generation rate (g) and solute distribution volume in the dry state (V<sub>D</sub>) increased with increases in p<sub>1</sub> in both models, but there were some differences between the two models. When g was normalized by V<sub>D</sub>, it became relatively constant, irrespective of the p<sub>1</sub> value or model used (0.133 ± 0.029 mg/min/l by the 2CM and 0.132 ± 0.029 mg/min/l by the RBF for UN; 0.0200 ± 0.0049 mg/min/l by the 2CM and 0.0198 ± 0.0048 mg/min/l by the RBF for Cr). The intercompartmental mass transfer coefficient (K<sub>c</sub>; liters/min) calculated by the 2CM decreased as p<sub>1</sub> increased (K<sub>c</sub> = –1.77·p<sub>1</sub> + 1.16, p < 0.0001, R = 0.999 for UN; K<sub>c</sub> = –0.847·p<sub>1</sub> + 0.556, p < 0.0001, R = 1.000 for Cr). The systemic blood flow (Q<sub>sys</sub>; liters/min) calculated by the RBF also decreased as p<sub>1</sub> increased (Q<sub>sys</sub> = –11.1·p<sub>1</sub> + 6.21, p < 0.0005, R = 1.000 for UN; Q<sub>sys</sub> = –5.22·p<sub>1</sub> + 2.90, p < 0.001, R = 0.999 for Cr). Since the RBF more frequently failed to solve the solute kinetics and since there was a difference in its Q<sub>sys</sub> values for UN and Cr, the 2CM was considered to be a superior model. When p<sub>1</sub> was extremely low, the 2CM could be transformed into a modified variable-volume one-compartment model (1CM) which presented a similar g/V<sub>D</sub> (0.133 ± 0.029 for UN; 0.0200 ± 0.0048 for Cr). This modified 1CM was considered to satisfy appropriate conditions for clinical application, since it is simpler than the 2CM and provides useful information on the dialysis dose.