N-nitrosodimethylamine (NDMA) is a disinfection byproduct that has been classified as probable human carcinogen by the US Environmental Protection Agency. According to the published literature, natural dissolved organic matter (DOM) can be a source of NDMA precursors in drinking water. New advances in chemical characterization of DOM with high resolution mass spectrometry (HRMS) are allowing researchers to understand these ultra-complex mixtures. The objective of this study is to investigate analytical methodologies based on HRMS to explore NDMA formation from natural waters. To this aim, different waters from drinking water reservoirs in Spain containing NDMA precursors (quantified by means of NDMA formation potential) in concentrations between 17 and 60 ng/L have been studied. The workflow includes DOM solid-phase extraction and Orbitrap analysis with and without chromatographic separation. Here, we show that the molecular composition of DOM across the studied drinking water reservoirs is correlated with the NDMA formation potential. In particular, we found that NDMA formation potential is associated with compounds with high hydrogen saturation (H/C ≥ 1.5), corresponding also to reservoirs with higher background nutrient concentrations and wastewater indicators. Further chromatographic fractionation did not allow better definition of these possible precursors as they were present in different fractions of the chromatogram, suggesting that they were isomerically complex. Copyright © 2019 Elsevier B.V. All rights reserved.