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Detection of drugs in tissue typically requires extensive sample preparation in which the tissue is first homogenized, followed by drug extraction, before the extracts are finally analyzed by LC/MS. Directly analyzing drugs in intact tissue would eliminate any complications introduced by sample pretreatment. A matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS(n)) method as been developed for the quantification of cocaine present in postmortem brain tissue of a chronic human cocaine user. It is shown that tandem mass spectrometry (MS(2) and MS(3) increase selectivity, which is critical for differentiating analyte ions from background ions such as matrix clusters and endogenous compounds found in brain tissue. It is also shown that the use of internal standards corrects for signal variability during quantitative MALDI, which can be caused by inhomogeneous crystal formation, inconsistent sample preparation, and laser shot-to-shot variability. The MALDI-MS(n) method developed allows for a single MS(3) experiment that uses a wide isolation window to isolate both analyte and internal standard target ions. This method is shown to provide improved precision [approximately 10-20 times reduction in percent relative standard deviation (%RSD)] for quantitative analysis compared to using two alternating MS(3) experiments that separately isolate the target analyte and internal standard ions., (2010 American Society for Mass Spectrometry. Published by Elsevier Inc. All rights reserved.)