There is a limit in the number of substances detected by commercially available reagents. It is therefore important to have other, complementary techniques. Liquid chromatography-tandem mass spectrometry (LC-MS-MS) may offer one possibility. An LC-MS-MS procedure based on the detection of positive ions after atmospheric pressure chemical ionization (APCI) was developed for direct measurement of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine in urine. It was compared with Online Amphetamines. The LC-MS-MS methodology showed improved sensitivity (1 00-ng/mL cutoff and specificity with a coefficient of variation of 10%. It was compared to the immunochemical analysis using 1000 clinical patient urine samples. The positive samples were confirmed by gas chromatography-mass spectrometry. The LC-MS-MS method detected almost four times as many samples positive for MDMA compared to the immunochemical method, with no false positives and one false negative. Our study suggests that LC-MS-MS offers an alternative to immunochemical methods in drug of abuse screening.