As a consequence of climate change, increased precipitation in winter and longer periods of decreased precipitation in summer are expected to cause more frequent episodes of very high or very low river discharge in the Netherlands. To study the impact of such extreme river discharge conditions on water quality, toxicity profiles and pollutant profiles were determined of suspended particulate matter (SPM) collected from Rivers Meuse and Rhine. Archived (1993-2003) and fresh (2009-2011) SPM samples were selected from the Dutch annual monitoring program of the national water bodies (MWTL), representing episodes with river discharge conditions ranging from very low to regular to very high. SPM extracts were tested in a battery of in vitro bioassays for their potency to interact with the androgen receptor (AR), the estrogen receptor (ER), the arylhydrocarbon receptor (AhR), and the thyroid hormone transporter protein transthyretin (TTR). SPM extracts were further tested for their mutagenic potency (Ames assay) and their potency to inhibit bacterial respiration (Vibrio fischeri bioluminescence assay). Target-analyzed pollutant concentrations of the SPM samples and additional sample information were retrieved from a public database of MWTL results. In vitro toxicity profiles and pollutant profiles were analyzed in relation to discharge conditions and in relation to each other using correlation analysis and multivariate statistics. Compared to regular discharge conditions, composition of SPM during very high River Meuse and Rhine discharges shifted to more coarse, sandy, organic carbon (OC) poor particles. On the contrary, very low discharge led to a shift to more fine, OC rich material, probably dominated by algae. This shift was most evident in River Meuse, which is characterized by almost stagnant water conditions during episodes of drought. During such episodes, SPM extracts from River Meuse demonstrated increased potencies to inhibit bacterial respiration and to compete with thyroid hormone to bind to TTR, possibly due to the presence of fycotoxins. Meanwhile concentrations of polychlorobiphenyls (PCBs) in SPM were also increased. Very high River Meuse discharges on the other hand corresponded to increased androgenic and AhR agoniztic responses, which coincided with increased PAH levels and PAH-related in vivo risk estimates (i.e. multi-substance potentially affected fraction of species; msPAF). In River Rhine, very high discharges also corresponded to increasing androgenic potencies in SPM. Concentrations and corresponding msPAF values of PAHs (and metals), however, decreased with very high discharges in River Rhine in contrast to River Meuse. Mutagenicity was observed for SPM extracts from River Rhine collected during all discharge conditions, except during regular discharge. Aggregated toxicity index values, which were useful to identify toxicity profiles deviating from the generally observed pattern, did not correlate with river discharges, probably due to opposite effects of discharge conditions on different bioassay responses. In conclusion, SPM quality and related in vivo risk estimates changed during very low or very high discharge conditions but the changes were specific for the different toxic endpoints and pollutants in the different rivers. Moreover, bioassay responses to a series of consecutively collected samples from River Rhine during the Christmas flood of 1993 indicated that SPM quality is variable within a single episode of extreme discharge.