There is a risk of 'ecological surprises' if multiple potentially interacting stressors are managed individually, which is a question attracting significant current interest. Habitat degradation and species introductions are major threats to global biodiversity, and riverine fish are among the most threatened taxa in the world. Our interest was whether the presence of non-native species can affect native fish sensitivity to water quality deterioration in a large region in northeastern Spain (99,700km2, 15 catchments, 530 sites). We used a 'base model' with geographical and hydro-morphological variables, which are the major shaping factors in rivers. We tested whether water pollution, non-native species, or their interaction provided an improved understanding of patterns of distributions and health measurements of the twelve most common native species. There was little evidence that variation in native species abundance, where they occurred, the presence of diseases and changes in mean fish length or body condition was affected by water deterioration, the presence of non-native species, or their interaction. The disease rate and occurrence of native species might be affected, to a minor degree, by water quality changes and the presence of non-native species. Environmental conditions between sites with and without non-native fish differed in the condition of riparian areas and in water quality. Based on presence-absence data and changes in abundances through weighted average equations we also derived potential safe levels of salinization, nutrient pollution, and pH for the native fish. Overall, additive effects of stressors prevail over interactions, and the restoration of natural hydro-morphology in rivers is likely to be the most effective management approach to improving the prospects for the native fish fauna.