A sensitive method is introduced to detect selected pharmaceutical residues and polar pesticides with UHPLC–MS in water samples of different origin. Active or passive water sampling was combined with a laboratory solid-phase extraction cleanup and stable isotope dilution analysis. Recovery experiments demonstrated that the internal standard correction performed well for the compensation of matrix effects. Besides, the original targeted analysis approach was expanded by non-target analysis of the samples with only one more consecutive injection run needed. The key benefits of this multi-residue analysis are:•Targeted analysis and quantification combined with non-target analysis on a micro-scale UHPLC–MS system usually employed for qualitative analysis only.•The internal standards for targeted analysis were used in non-target runs to calculate the partition coefficient logP of unknown substances employing the retention time index (RTI).•The filtering of database hits for two criteria (exact mass and partition coefficient) significantly reduced the list of suspects and at the same time rendered it possible to perform non-target analysis with lower mass accuracy (no lock-spray) in the range of 20–500ppm.