Forensic and clinical toxicological screening procedures are more and more employing LC-MS/MS techniques with information dependent acquisition (IDA) approaches. It is known that complexity of sample and settings of IDA might prevent important compounds from being triggered. Therefore, data independent acquisition methods (DIA) should be more suitable for systematic toxicological analysis (STA). The DIA method sequential window acquisition of all theoretical fragment-ion spectra (SWATH) which uses Q1 windows of 20-35 Da for data independent fragmentation, was systematically investigated for its suitability for STA. Quality of SWATH generated mass spectra were evaluated with regard to mass error, relative abundance of the fragments and library hits. With the Q1 window set to 20-25 Da, several precursors pass Q1 at the same time and are fragmented thus impairing the library search algorithms to a different extent: forward fit was less affected than reverse fit and purity fit. Mass error was not affected. Relative abundance of the fragments was concentration dependent for some analytes and was influenced by co-fragmentation, especially of deuterated analogues. Also the detection rate of IDA compared to SWATH was investigated in a forced coelution experiment (up to 20 analytes coeluting). Even using several different IDA settings it was observed that IDA failed to trigger relevant compounds. Screening results of 382 authentic forensic cases revealed that SWATH’s detection rate was superior to IDA, which failed to trigger about 10% of the analytes.