The propionyl, trimethylsilyl, trifluroacetyl, and heptafluoroacyl derivatives of 6-acetylmorphine (6-AM) were evaluated with respect to optimal method performance, derivative stability, and methods characterization for use in gas chromatographic-mass spectrometric (GC-MS) analysis with electron ionization mode and selected ion monitoring. The most common potential interferences and compatibility with other derivatives when used on the same GC-MS were determined for the derivatizing reagents. The propionyl, trimethylsilyl, and trifluroacetyl derivatives produced adequate stability, accuracy, and precision for the method. The 6-AM derivatization with commercially available propionic anhydride generated a relatively small amount of 6-AM-propionyl derivative from the free morphine present in a specimen. The trimethylsilyl derivative obtained by the reaction with MSTFA did not require incubation, was the easiest to prepare, and had the highest potential for use on an automated sample-preparation device. An important advantage of derivatization with MSTFA is elimination of the possibility of heroin decomposition to 6-AM that is due to incubation at elevated temperature.