A simplified preconcentration method for a range of ultra-trace level pharmaceuticals in natural waters has been developed. Solid phase extraction was performed on-line using a micro-reversed-phase monolithic silica column, allowing for very rapid trace enrichment from large volume (500ml) samples with minimal sample handling. Acceptable recoveries of >70% were obtained for the majority of compounds investigated and the monolithic columns could be washed and conditioned on-line with no sample carryover and used reproducibly for up to eight extractions each. The on-line SPE-LC-UV method was coupled to electrospray ionisation ion trap mass spectrometry (ESI-MS) to increase both selectivity and specificity. Detection limits were determined in spiked river and tap water samples and found to lie in the low ng/l region using sample volumes of 500ml, loaded at a flow rate of 10ml/min, and therefore, were suitable for ultra trace analysis.