Few methods are available for comprehensive organophosphate flame retardants (PFRs) detection in water and wastewater. Gas chromatography has been employed previously, but this approach is less selective, not amenable for use with deuterated standards and can suffer unfavorable fragmentation. Ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-QqQ-MS/MS) has become the most promising platform, already applied successfully for analysis of selected PFRs in some environmental matrices like water and wastewater. However, the presence of some interferences from the dissolvent, the equipment and the used materials should be taken into account. The procedure involves: •The first determination of PFRs by UHPLC-QqQ-MS/MS using a trap column to distinguish the interferences coming from the instrument and mobile phases.•The optimization of the LC separation to distinguish all target compounds and their interferences.•This method coupled to a solid-phase extraction (SPE) improve the detection and quantification of PFRs.