Due to the large number of basic therapeutic and illicit drugs, systematic toxicological analysis has widely been performed with liquid chromatography coupled to mass spectrometry using positive electrospray ionization. However, there exists a smaller number of drugs, typically acidic drugs, which require the use of negative electrospray ionization either via a separate injection or polarity switching. Here, targets relating to salicylic acid and ibuprofen in positive electrospray ionization were determined through a metabolomics-driven retrospective investigation of forensic casework. Samples were previously screened using liquid chromatography coupled with high-resolution mass spectrometry with quantification of target analytes performed using liquid chromatography with tandem mass spectrometry. Of the 1717 whole-blood samples submitted between 2014 and 2019, 48 were positive for salicylic acid (1.1-1400 mg/kg) and 78 for ibuprofen (1-46 mg/kg). Based on the retrospective analysis, 19 and 90 targets were identified for salicylic acid and ibuprofen, respectively. For targets of salicylic acid, the protonated adduct of salicyluric acid ([M+H]+, m/z 196.0605) was present in 89.6% (n = 32) of the salicylic acid positive cases while the [M+HCOOH+CH3CN+Ca-H]+ adduct (m/z 264.0179) of salicylic acid was present in all positive samples with concentrations above 66 mg/kg salicylic acid. Similarly, the [M + 2Na - H]+ adduct (m/z 251.1018) of ibuprofen was present in 98.7% (n = 77) of positive cases and was present in all samples with concentrations above 3 mg/kg ibuprofen.