BACKGROUND Approximately 6% of new-onset seizures are drug-related, but there is currently no reliable way to determine if a seizure is drug-induced. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful tool that allows simultaneous detection of numerous analytes of diverse chemical nature in patient samples. This allows a single analysis to incorporate many compounds relevant to a particular clinical presentation, such as suspected drug-induced seizures. We investigated whether results from a seizure panel using LC-MS/MS could affect patient care. METHODS We developed a semiquantitative LC-MS/MS assay to detect 12 chemically diverse drugs implicated in drug-related seizures. We collected leftover serum and plasma samples from patients who had seized, performed solid-phase extraction, and analyzed the samples using a hybrid triple quadrupole/linear ion trap mass spectrometer. After assembling a team of medical and toxicology experts, we developed and used a scoring system to determine whether the results of the seizure panel would have affected patient treatment in each case where a drug was detected. RESULTS In an analysis of 157 samples from patients who seized, 17 (11%) were found to be positive for a drug on the seizure panel. The team of experts determined that the test results probably or definitely would have affected treatment in 7 (41%) of these cases. CONCLUSIONS A test that detects the presence of drugs implicated in drug-induced seizures can help physicians determine if an unexplained seizure is drug-related and thus potentially better direct patient care. Additionally, LC-MS/MS is an effective tool for answering clinically driven questions.