A solid-phase extraction coupled to high performance liquid chromatography-tandem mass spectrometry(LC-MS/MS)was developed for determination of six lipophilic marine toxins, including OA, DTX₂,YTX,DTX₁, AZA₁ and SPX₁ in shellfish.Methods Homogenised tissues were extracted twice with 80% methanol in water, and resulting extracts were cleaned-upon StrataTM-X solid phase extraction column and eluted with MeOH solutions containing 0.3% NH₄OH,followed by filtering through a ultra-filter centrifuge tube. The target components were separated and gradient eluted on a XTerraMS C₁₈ column using mobile phases of MeCN/water and water, both phase containing 6.7mmol/L NH₄OH, and simultaneously quantified by switching alternatively between positive ions and negative ions under multiple reactions monitoring mode. The matrix-matched external standard calibration were carried out for the quantitative analysis. Results The limits of quantification ranged from 0.2 to 1.0 μg/kg for six marine lipophilic toxins. The calibration curves were linear in the respective concentration ranges, with the correlation coefficients >0.995. The average recoveries for toxins at three concentration levels were 78.8%-116%, and their relative standard deviation varied between 3.8% and 14.5%.The method was applied to analyze several shellfish samples, but no one was positive. Conclusion The method developed was selective, sensitive and accurate, and was suitable for analysis and confirmation of marine lipophilic toxins in shellfish.