Depending on the very low therapeutic doses of clonidine and the resulting low blood levels (in the pg/ml range), for quantitative determinations in body fluids only methods of necessary selectivity as well as corresponding sensitivity can be employed successfully. Furthermore, the method should also be suited for the rapid processing of large sample numbers generated e.g. during clinical studies evaluating pharmacokinetics and/or the bioavailability/bioequivalence. Thus a gas chromatographic/mass spectrometric assay was developed employing fused-silica, bonded-phase capillary columns, chemical ionization with ammonia as a selective reagent gas in combination with the registration of preselected, characteristic negative ions (SIR, NICI) and a deuterated internal standard. Therefore, the method proves to be exceptionally selective and sensitive: a lower limit of detection of 10 pg/ml plasma is reached, the calibration curve is linear in the 25-1500 pg/ml range and the recovery from blood exceeds 90%. The assay has been successfully approved in several clinical studies, whereby especially the simple sample preparation led to very short times for analysis.