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Plasma stability plays an important role in drug discovery and development. Unstable compounds tend to have rapid clearance and short half-life, resulting in poor in vivo performance. This paper examines the variables that affect the plasma stability assay results, including substrate concentration, %DMSO, plasma concentration, enzyme activity upon incubation and batch variation. The results show that plasma stability can accommodate a wide range of experimental conditions. Relatively minor differences in results are produced with major differences in conditions. Significant batch-to-batch variations were observed for rat plasma. We selected the following conditions: 1 μM substrate concentration, 2.5% DMSO, and 50% dilution of plasma in pH 7.4 buffer. Plasma stability can be used as a diagnostic assay when compounds are unexpectedly rapidly cleared, as a special assay when structural classes contain groups that may be susceptible to plasma enzyme hydrolysis, or as general screen for compounds if resources are available. Plasma stability assay has many applications in drug discovery: to alert teams to labile structural motifs, to prioritize compounds for in vivo studies and to screen prodrugs and antedrugs.