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The Klamath-Siskiyou Ecoregion (KSE) of southwest Oregon-northern California, USA has globally exceptional biodiversity but is experiencing mounting pressures from climate change and land uses. We conducted an ecoregional conservation assessment of the KSE and the Siskiyou Crest subregion (SCS), a proposed climate refugium within the KSE, to integrate protected area priorities with climate change planning and fire risk reduction for communities. Both areas contained very low levels (<30%) of protection (GAP status 1, 2) for nearly all land cover types (n=22), including serpentine substrates where endemic plants are highly concentrated, older forests with potential refugia properties, and habitat for Northern Spotted Owl (Strix occidentalis caurina) and Pacific fisher (Pekania pennanti). At the ecoregional scale, high severity fire levels were proportionately similar across GAP land-use status (“managed” vs. protected). However, high severity fire was lowest for protected areas at the subregional scale reflective of potential refugium properties. Most fuel treatments by federal agencies were >1-km from nearest structures, far removed from effective community fire protection in both locales. The relatively higher-elevation SCS is projected to maintain refugia properties (cooler, wetter) for longer periods than the KSE; however, that function may dissipate toward the end of the century and under a higher emissions scenario. Stepped up protections especially of potential refugia combined with fire risk reduction of the built environment are urgently needed to prevent unprecedented losses.