To investigate the error possibly contained in the single sample distribution volume method for the determination of renal clearance, a mathematical model was applied to describe the effect of changes in distribution volume, clearance, intravascular space, intracompartmental exchange and the time point of blood sampling. The method was found to be valid only under well-defined circumstances (T_opt = 45 ± 5 min, Cl = 390 ± 50 ml/min, V_d = 16.7 ± 41, α = 0.05 · V₁ ml/min, V₁/V_d = 0.5 ± 0.05) as shown in sample calculations. Two-compartment model-based error calculations demonstrate that this technique implies at best an uncertainty of ± 10% or more. Whilst it can be used preferably in healthy, normal-weight adults, it is not applicable, without error, under all other circumstances.