For populations of cutthroat trout Oncorhynchus clarkii, isolation in headwater streams may provide protection from invasion by nonnative species but also may enhance a population's vulnerability to extirpation. We assessed the risk of extirpation for eight Colorado River cutthroat trout O. clarkii pleuriticus populations isolated above water diversion structures in the North Fork Little Snake River drainage, Wyoming. The populations had been isolated for 25–44 years, occupied headwater streams that ranged from 850 to 6,100 m in length, and had adult populations that were estimated to range from 12 to 506 fish. Adult population sizes were compared with published occurrence models to identify populations that may be at risk of extirpation. One population had experienced an 11% annual rate of decline in abundance over the past 29 years, but there was no evidence of declines among the other populations. There was evidence of recruitment failure for age‐1 fish in two of the smaller populations. Abundance estimates and published logistic regression models consistently identified the largest tributary in the drainage as being the most likely to support a Colorado River cutthroat trout population in the future and the smallest tributary as being the least likely to support a population in the future. The analyses indicated that isolated populations may persist for decades, but small effective population sizes can make populations vulnerable to eventual loss of genetic variability and to extirpation.