We have investigated the potential of capillary-column-switching liquid chromatography coupled to tandem mass spectrometry (cLC-MS-MS) for the quantitative on-line trace analysis of target compounds in aqueous solutions. The technical design of the nano-scale cLC system developed at our Institute for peptide and protein identification has been tested and evaluated for the direct trace analysis of drugs in water samples. Sulphametoxazole, bezafibrate, metoprolol, carbamazepine and bisoprolol occurring frequently in Dutch waters, were selected as test compounds. Adequate conditions for trapping, elution and MS-MS detection were investigated by employing laboratory made 200 microm i.d. capillary columns packed with 5 microm aqua C18 material. In the final cLC-MS-MS conditions, a 1 cm length trapping column and a 4 cm length analytical column were selected. Under these conditions, the target compounds could be directly determined in water down to a level of around 50 ng/l employing only 25 microl of water sample. Validation was done by recovery experiments in ground-, surface- and drinking-water matrices as well as by the analysis of water samples with incurred residues and previously analyzed with a conventional procedure involving off-line solid-phase extraction and narrow-bore LC with MS-MS detection. The new methodology provided recoveries (50-500 ng/l level) between 50 and 114% with RSDs (n = 3, each level) below 20% for most of the compounds. Despite the somewhat less analytical performance in comparison to the conventional procedure, the on-line approach of the new methodology is very suitable for screening of drugs in aqueous samples.