The Columbia River basin is a large transboundary basin located in the Pacific Northwest. The basin spans seven US states and one Canadian province, encompassing a diverse range of hydroclimates. Strong seasonality and complex topography are projected to give rise to spatially heterogeneous climate effects on unregulated streamflow. The basin’s water resources are economically critical, and regulation across the domain is extensive. Many sensitivity studies have investigated climate impacts on the basin’s naturalized hydrology; however, few have considered the large role of regulation. This study investigates where and when regulation affects projected changes in streamflow by comparing climate outcomes across 80-member ensembles of unregulated and regulated streamflow projections at 75 sites across the basin. Unregulated streamflow projections are taken from an existing dataset of climate projections derived from Coupled Model Intercomparison Project version 5 Global Climate Models. Regulated streamflow projections were modeled by the US Army Corps of Engineers and the US Bureau of Reclamation by using these unregulated flows as input to hydro-regulation models that simulate operations based on current and historical water demands. Regulation dampens shifts in winter and summer streamflow volumes. Regulation generally attenuates changes in cool-season high flow extremes but amplifies shifts in warm-season and annual high flow extremes at historically snow-dominant headwater reservoirs. Regulation reduces dry-season low flow changes in headwater tributaries where regulation is large but elsewhere has little effect on changes in low flows. Results highlight the importance of accounting for water management in climate sensitivity analysis particularly in snow-dominant basins.