A rapid, sensitive, and specific method for the determination of opiates and cocaine and metabolites in urine, plasma, and blood was established. A one-step extraction followed by liquid chromatography-electrospray ionization tandem mass spectrometry operating in multiple reaction monitoring mode was used. Two chromatographic runs were performed, each in less than 6 min. The lower limit for accurate quantitative determination was 5 microg/L for cocaine and metabolites and 10 microg/L for opiates. Linearity was obtained from 10 to 1000 microg/L. Intraday (n = 6) and interday (n = 6) precisions and recoveries (n = 6) were determined at 10 or 25, 100, and 1000 microg/L concentrations. Precisions with a coefficient of variation less than 15% were obtained. Recoveries between 85 and 115% were determined.