In this study, sample preparation, cleanup, and analysis protocols were developed for tandem LC-MS determination of a wide variety of veterinary drug residues in seafood tissue samples. This cleanup protocol was effective for removal of both fats and phospholipids. Two types of tissue samples, shrimp (prawn) and salmon, were chosen to demonstrate the suitability of the methodology. Samples were treated with an acidified acetonitrile/water solvent to precipitate proteins and to extract the veterinary drugs of interest. Then, a simple cleanup was performed using a novel SPE device, the Oasis PRiME HLB Cartridge. Representative compounds were chosen from major classes of veterinary drugs including tetracyclines, fluoroquinolones, sulfonamides, macrolides, beta-lactams, NSAIDS, steroids and beta-andrenergics. These compounds were spiked into the seafood samples prior to extraction and cleanup.