The Division of Drug Analysis of the U.S. Food and Drug Administration In St. Louis, MO, has screened more than 1400 drug samples for potential generic drug fraud by a combination of physical, instrumental, and chemical techniques. The approach to fraud centered around the analysis of exciplents as opposed to the normal approach of analysis of active Ingredients. Approximately 80% of the drug formulation pairs (Innovator and generic) submitted for bloequlvalence testing could be differentiated by a combination of physical and instrumental analysis, mainly thermogravimetrlc analysis (TGA) and Fourier-transform Infrared (FTIR) spectrometry. TGA proved to be the single most useful instrumental technique to determine differences In formulations. Liquid chromatography, gas chromatography, chemical tests, and polarizing microscopy were found to be the most useful tools to differentiate formulations that could not be resolved by FTIR, TGA, or physical comparisons. Xray powder diffraction and nuclear magnetic resonance spectroscopy were found not to be useful techniques to differentiate formulations. No clear-cut evidence of direct fraud was found, but Inconsistencies and suspicious samples were noted. Follow-up inspections based on the laboratory findings will probably occur. The procedures discussed In this article could be streamlined and made more efficient for examining large numbers of potential problem formulations.