Atmospheric general circulation models (GCMs) used to project climate responses to increased CO2 generally omit irrigation of agricultural land. Using the NCAR CAM3 GCM coupled to a slab-ocean model, we find that inclusion of an extreme irrigation scenario has a small effect on the simulated temperature and precipitation response to doubled CO2 in most regions, but reduced warming by as much as 1°C in some agricultural regions, such as Europe and India. This interaction between CO2 and irrigation occurs in cases where agriculture is a major fraction of the land surface and where, in the absence of irrigation, soil moisture declines are projected to provide a positive feedback to temperature change. The reduction of warming is less than 25% of the temperature increase modeled for doubled CO2 in most regions; thus greenhouse warming will still be dominant. However, the results indicate that land use interactions may be an important component of climate change uncertainty in some agricultural regions. While irrigated lands comprise only ∼2% of the land surface, they contribute over 40% of global food production. Climate changes in these regions are therefore particularly important to society despite their relatively small contribution to average global climate.