Matrix effects are well-known challenges for accurate and comparable measurements with liquid chromatography (LC) electrospray ionization mass spectrometry (ESI-MS). This study describes a three-step method to evaluate and compensate for matrix effects in enriched wastewater extracts using LC ESI-high-resolution MS (HRMS). As a first step, the "dilute and shoot" approach was used to determine the optimal relative enrichment factor (REF) for a direct comparison between wastewater influent (REF 10) and effluent (REF 50) extracts. However, the rapid decrease in the number of non-target compounds detected with increasing dilution leads to the need for a correction of the matrix effect for analyzing samples with higher REFs. As a second step, the observed matrix effect at higher REFs was corrected by the retention time-dependent matrix effect. A new scaling (TiChri scale) of the matrix effect was introduced, which demonstrates that the total ion chromatogram (TIC) predicts the matrix effect as effectively as post-column infusion (PCI) approaches; thus, the average median matrix effect was improved from -65 to 1% for influent (REF 100) and from -46 to -2% for effluent extracts (REF 250). The TIC traces for concentrated (REF 250) influent and effluent samples were successfully used to correct the matrix effects and allowed the extent of micropollutant degradation in three WWTPs to be quantified. As a final step, the residual structure-specific matrix effect was predicted and corrected by quantitative structure-property relationships (QSPR), which led to a further correction of the matrix effect to 0 ± 7% for 65 compounds.