A quantitative method is reported for the determination of imipramine in plasma samples in the low nanogram and subnanogram range. The sensitivity and precision of the technique, which involves high pressure liquid chromatography and direct probe field ionization mass spectrometry, are approximately an order of magnitude greater than are offered by gas chromatography mass spectrometry with selected ion monitoring using deuterated or other types of internal standards. [2H6]Imipramine, labeled in the ethylene bridge and in the aromatic rings, serves as the isotopic diluent. The method has been used for the determination of the comparative bioavailabilities of two different commercial preparations of imipramine. In these tests, subjects ingested a 25 mg tablet of one or the other drug preparation together with a solution containing an equivalent amount of imipramine deuterated in the ethylene bridge ([2H2]imipramine). The latter served as an internal check for intrasubject variability in absorption of the imipramine tablets. Typical results from one of the subjects are presented.