Therapeutic drug monitoring of antipsychotic drugs has become more and more important in recent years, and a well-organized therapeutic drug monitoring service with fast turn-around times is very important. Therefore, an analytical method coupling high-performance liquid chromatography to mass spectrometry with electrospray ionization in the positive mode was established in our laboratory. Amitriptyline, citalopram, clomipramine (including norclomipramine), desipramine, dibenzepin, doxepin (including nordoxepin), escitalopram, flupentixol, fluphenazine, fluvoxamine, imipramine, nortriptyline, opipramol, pipamperone, reboxetine, thioridazine, trimipramine and zuclopenthixol were separated on a reversed-phase C18 column. The mobile phase consisted of acetonitrile and ammonium acetate buffer pH 4. Because of different organic solvents used for the liquid-liquid extraction and the different volumes of mobile phases in which the residues were dissolved, four analytical systems had to be applied. Within the run-time of maximal 10 minutes the 13 antidepressant and five neuroleptic drugs were baseline separated on the corresponding mass-to-charge track. The calibration range of each drug was linear, all between-day coefficients of variation were below 7% and the recovery rates were between 60 and 103%. Using 1 ml of serum, the lower limits of quantification were between 1.2 and 54 nmol/l for the different drugs and below the therapeutic range for each of the different drugs.