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Climate change is expected to have strong effects on river systems and their biota. It is unlikely that a changing climate will be the only stressor on river systems to increase in the future. Human population growth will necessitate increased resource use including agricultural intensification. Understanding how climate change will interact with agricultural intensification to affect river systems is important for effective management. We used a spatially explicit, habitat-based life cycle model, Ecosystem Diagnosis and Treatment (EDT), to examine the effects of climate change and agricultural intensification scenarios on the performance of steelhead Oncorhynchus mykiss in a Columbia River Subbasin. Climate change had strong negative impacts on basin-wide abundance, habitat capacity, productivity, and life-history diversity of steelhead, with the largest impacts under the most severe climate scenarios. Agricultural intensification also had strong negative effects on steelhead performance, particularly under the most severe scenario of complete removal of riparian buffers in crop production areas. When combined, both stressors had interactive effects on steelhead. The egg incubation stage was the most vulnerable to both stressors. Spawning adults were also strongly affected by climate change, whereas overwintering parr were affected by agricultural intensification. EDT modeling allowed an identification of areas within the subbasin most vulnerable to these stressors, as well as areas that are strongholds of productivity under future conditions. Finally, model results revealed that the most important areas to protect against both climate and agricultural change are not necessarily the same as those identified as high priority areas for protection and restoration under current conditions.