The present paper describes an analytical method for the determination of 2 widely administered anticancer drugs, ifosfamide and cyclophosphamide, contained in sewage sludge. The method relies on the extraction from the solid matrix by pressurized liquid extraction, sample purification by solid-phase extraction and analysis by ultra high performance liquid chromatography coupled with tandem mass spectrometry. The different parameters affecting the extraction efficiency were optimized using an experimental design. Solvent nature was the most decisive factor for the extraction but interactions between some parameters also appeared very influent. The method was applied to seven different types of sludge for validation. The performances of the analytical method displayed high variability between sludges with limits of detection spanning more than one order of magnitude and confirming the relevance of multi-sample validation. Matrix effect has been determined as the most limiting analytical step for quantification with different extent depending on analyte and sludge nature. For each analyte, the use of deuterated standard spiked at the very beginning ensured the complete compensation of losses regardless of the sample nature. The suitability of the method between freshly spiked and aged samples has also been verified. The optimized method was applied to different sludge samples to determine the environmental levels of anticancer drugs. The compounds were detected in some samples reaching 42.5 μg/kgDM in ifosfamide for the most contaminated sample.