A sensitive, precise, and accurate liquid chromatography-mass spectrometry (LC-MS-MS) method was developed to quantitate cocaine and cocaine metabolites, which were simultaneously extracted from suspected drug-positive meconium samples using solid-phase extraction. The ability to analyze cocaine and multiple cocaine metabolites in meconium makes this method a powerful tool for the study of cocaine exposure and metabolism in neonates. Of 22 samples, only 1 did not show the presence of cocaine or any metabolite of cocaine. The identified metabolites varied both qualitatively and quantitatively between samples. Ecgonine appears to hold the most promise as a diagnostic marker compound for neonatal cocaine exposure as this metabolite was present in 21 of 21 of the positive samples tested, and at a relatively high median concentration. However, a core group of eight metabolites (present in at least 20 of 21 positive samples) was identified that appears to possess the greatest utility for determining cocaine exposure. Finally, the use of this method for assessment of the magnitude of fetal cocaine exposure was demonstrated.