Isotachophoresis seems a likely candidate for a reference method, as it is more accurate and precise than common routine methods. The response is highly linear and depends on a well defined transport number of the leading ion, stability of the driving current, mobility of the separand, which is well controlled by the leading electrolyte and the use of a high-resolution detector. The suitability of isotachophoresis as a reference method was investigated for the determination of sodium in human serum. The operational conditions were 0.01 M K+/citrate (leading electrolyte) at pH 5.5 and 0.01 M creatinine X HCl (terminating electrolyte). Both n-butylamine and ammediol could be used as internal standards. The calibration graph constructed from standard solutions, diluted by weight with the internal standard, yielded a correlation coefficient of 0.99994 (n = 50) in the working range. The method seems especially useful for the determination of any ionic solute in, e.g., clinical samples (lithium, calcium, creatinine or drugs).