For over 30 y, a mouse bioassay has been used to monitor paralytic shellfish poisoning (PSP) toxicity in shellfish harvested along the coast of Uruguay. Although providing a good controlmechanism for the safety of shellfish consumers, the assay is known to have several disadvantages. To assess the potential for use of liquid chromatography with fluorescence detection, a study was conducted to analyze shellfish samples harvested over a 20-y period using this alternative method. Mussels and clams were analyzed using the AOAC Official Method 2005.06 with results compared with those obtained from the original mouse bioassay and used to determine the presence of specific toxin congeners. The chromatographic results from nontoxic samples indicated no specificity issues resulting fromthe potential presence of naturally fluorescent coextractives but with complex and variable toxin distributions in samples designated PSP-positive by the bioassay. Although some species-related differences in toxin profile may be attributed to differences in shellfish metabolism, clear profiles were noted in shellfish harvested during two distinct phytoplankton blooms of Gymnodinium catenatumand Alexandriumtamarense. The work therefore showed evidence for the presence of awide range of toxin congeners and the need for any replacement quantitative method to be fully capable of analyzing the major toxins of importance. Some differences between the toxicity results determined by the twomethods indicated, however, the need for further investigations to assess the potential presence of other toxins, which may remain undetected using AOAC 2005.06.