We investigated the relationships between the ecological status of wadeable rivers and the intensity of various stressors related with hydromorphological alterations, nutrient, and organic matter contaminations. The French invertebrate-based multimetric index (I2M2), which efficiently responds to the effects of both physical and chemical and hydromorphological stressors, was used as descriptor of river reach ecological status. We developed a model focusing on the effects of hydromorphological and physical and chemical stressor gradients on the I2M2 in different physiographic contexts. The potential confounding effects of natural geographic conditions and watershed scale pressure gradients were taken into account and neutralized by gathering watersheds into homogeneous clusters integrated as an interaction factor in the model. Whatever effects were considered (general or within-spatial clusters), the I2M2 was impaired similarly by the same stressor types, being negatively influenced by an increase in BOD5, ammonium, nitrite, nitrate, and total phosphorus concentrations. The I2M2 was also negatively influenced by variables describing hydromorphology at the reach scale, especially by the 'loss of sinuosity,' 'increasing rates of bank erosion,' 'flow reductions,' and 'alteration of pool/riffle succession.' The I2M2 was generally more strongly impaired by physical and chemical pressures than by hydromorphological alterations.