We use regional climate model (RCM) simulations from the North American Regional Climate Change Assessment Program (NARCCAP) to evaluate implications of climate change for the discharge of the Colorado River in the mid-21st century. We compare historical RCM simulations and simulations from their host global general circulation models (GCMs) to one-eighth degree gridded observations of precipitation, surface air temperature, and runoff (generated by the Variable Infiltration Capacity (VIC) land surface model forced with gridded observations) for the historical period 1970–1999. The RCMs capture the primary features of observations better than their host GCMs in part because of their ability to better represent strong upward lift in topographically complex regions. Although the RCMs do not significantly improve the simulation of precipitation, their ability to better represent surface temperature in mountainous regions has important effects on simulations of evapotranspiration, snowpack, and runoff. In the Colorado River basin, projected mid-21st century runoff changes are mostly impacted by the combination of snow cover change in winter, temperature change in spring, and precipitation change in summer. In particular, the response of cold season temperatures in headwater streams is key to determining the basin's susceptibility to a warming climate. Because of the cooler temperature and higher snowline in RCMs relative to GCMs, the RCMs project less warming in the spring and thus generate smaller decreases in runoff, both during spring and annually, as compared with GCMs. Changes in surface air temperature, runoff, and snow water equivalent at high elevations all indicate that headwater streams of the Colorado River are less susceptible to a warming climate in climate change simulations that use RCMs than in simulations that use GCMs. Nonetheless, the 50 km NARCCAP grid resolution has some limitations in resolving orographic effects, which suggests that there may remain residual biases in the climatic sensitivity of the RCM simulations.