Specifically, the project compared and evaluated the efficiency, accuracy, sensitivity, and breadth of the new LC-TOF-MS screening method with a laboratory’s current screening approach. A cost-benefit analysis of the new screening method was also conducted. Following the development, optimization, and validation of the new LC-TOF-MS method, it was used to analyze several hundred actual forensic cases to determine whether it identified more compounds than the laboratory’s current screening approach. The screening methods were compared on sample volume required, number and breadth of drugs identified, time for preparation and extraction, time to analyze the evidence, time for data analysis, time for technical and administrative reviews of data, and total costs. Overall, case comparison studies showed that LC-TOF-MS analysis detected compounds not detected with current screening protocols of immunoassay and basic drug screening by GC-MS/NPD. The most notable compounds identified were buprenorphine, gabapentin, and 6-AM. The identification of common target compounds occurred at lower concentrations than with current screening protocols. In addition, the validated method can reduce costs in the long-term while reducing case backlogs and/or case turnaround. This report suggests that other government toxicology laboratories can use the in-depth method development, optimization, and validation of the current project to guide them in their testing and policy decisions. Such activities currently underway are reported.