Effective conservation of Cutthroat Trout Oncorhynchus clarkii lineages native to the Rocky Mountains will require estimating effects of multiple stressors and directing management toward the most important ones. Recent analyses have focused on the direct and indirect effects of a changing climate on contemporary ranges, which are much reduced from historic ranges owing to past habitat loss and nonnative trout invasions. However, nonnative trout continue to invade Cutthroat Trout populations in the southern Rocky Mountains. Despite management to isolate and protect these native populations, nonnatives still surmount barriers or are illegally stocked above them. We used data on the incidence of invasions by nonnative Brook Trout (BT) Salvelinus fontinalis and the rate of their invasion upstream to simulate effects on a set of 309 conservation populations of Colorado River Cutthroat Trout (CRCT) O. c. pleuriticus isolated in headwater stream fragments. A previously developed Bayesian network model was used to compare direct and indirect effects of climate change (CC) alone on population persistence versus the added effects of BT invasions. Although CC alone is predicted to extirpate only one CRCT population by 2080, BT invasions and CC together are predicted to completely extirpate 122 populations (39% of the total) if managers do not intervene. Another 113 populations (37%) will be at risk of extirpation after CC and invasions, primarily owing to stochastic risks in short stream fragments that are similar under CC alone. Overall, invasions and CC will reduce the number of stream fragments that are long enough to buffer CRCT populations against negative genetic consequences and stochastic disturbances by 48, a decrease of 38% compared to CC alone. High priorities are (1) research to estimate how CC and human factors alter the incidence and rate of BT invasions and (2) management to prevent new illegal introductions, repair inadequate barriers, and monitor and address new invasions.