One of the most important and dangerous intoxication from seafood with algal toxins is paralytic shellfish poisoning (PSP) caused by a group of 18 neurotoxins. The closely related charged molecules act as potent sodium-channel blocker and cause paralytic symptoms such as respiratory insufficiency, in serious cases with fatal results. The broad toxicity range of different PSP toxins in a line with diverse PSP toxin profiles in dinoflagellates and the possibility of biotransformation of PSP toxins in marine organism has challenged analytical chemists to development accurate and reliable analytical methods. The separation of charged and highly water soluble organic compounds requires HPLC methods based on phosphate buffered ion-pair chromatography on reversed phases. Additionally, PSP toxins do not show any fluorescence or native UV activity and they are normally detected after chemical oxidation and conversion into fluorescent derivatives. The combination of ion-pair reagents and oxidation chemicals results in many disadvantages. Ion-pair former, phosphate buffer and derivatization chemicals prevent the on-line coupling of the separation technique to an MS spectrometer. The presented method is based on ion-exchange separation of PSP toxins using a cation and an anion exchange column. The separation of important toxin pairs (e.g. STX/NEO, GTX2/GTX3, and C1/C2) is easily achieved. Some advantages are evident. The lower concentration of buffers and missing ion-pair reagents allows the replacement of the complicated post-column oxidation unit by a simple electrochemical cell. The ion-exchange separation in combination with electro-chemical oxidation offers a cheap way for standard production, as the up-scaling to larger columns should be possible and the relatively expensive ion-pair reagents are not longer necessary. The mobile phases without ion-pair reagents allow the direct coupling of the HPLC to a mass spectrometer.