Technical Abstract: Introduction – Swainsonine, a polyhydroxy indolizidine alkaloid and known glycosidase inhibitor, is found in a number of different plants that cause a lysosomal storage disease known as locoism in the western US. Most recently swainsonine has been analyzed by LC-MS/MS after sample extraction and preparation from ion-exchange resins. Objective – To compare previously published sample preparation procedures with several new alternative procedures to provide methods using either commercially available solid phase extraction equipment or procedures which significantly reduce sample preparation time. Methodology – A previously reported and validated sample preparation method using ion-exchange resin was compared to methods either using a commercially available solid phase extraction cartridge, a solvent partitioning procedure or a single solvent extraction procedure using one of 2 solvents. Twenty different plant samples of varying swainsonine concentrations were prepared in triplicate and analyzed by LC-MS/MS. The measured concentration of swainsonine was then statistically compared between methods. Results – There were no statistically significant differences found between four of the five different sample preparation methods tested. Conclusion – A commercially available SPE cartridge can be used to replace the previously used ion-exchange resin for swainsonine analysis. For very rapid analyses the SPE procedure can be eliminated and a simple, single solvent extraction step used for sample preparation.