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The impacts of sea surface temperature (SST) anomalies and anthropogenic greenhouse gases on the likelihood of extreme drought occurring in the central United States in the year 2012 were investigated using large-ensemble simulations from a global atmospheric climate model. Two sets of experiments were conducted. In the first, the simulated hydroclimate of 2012 was compared to a baseline period (1986–2014) to investigate the impact of SSTs. In the second, the hydroclimate in a world with 2012-level anthropogenic forcing was compared to five “counterfactual” versions of a 2012 world under preindustrial forcing. SST anomalies in 2012 increased the simulated likelihood of an extreme summer precipitation deficit (e.g., the deficit with a 2% exceedance probability) by a factor of 5. The likelihood of an extreme summer soil moisture deficit increased by a similar amount, due in great part to a large spring soil moisture deficit carrying over into summer. An anthropogenic impact on precipitation was detectable in the simulations, doubling the likelihood of what would have been a rainfall deficit with a 2% exceedance probability under preindustrial-level forcings. Despite this reduction in rainfall, summer soil moisture during extreme drought was essentially unaffected by anthropogenic forcing because of 1) evapotranspiration declining roughly one-to-one with a decrease in precipitation due to severe water supply constraint and despite higher evaporative demand and 2) a decrease in stomatal conductance, and therefore a decrease in potential transpiration, with higher atmospheric CO2 concentrations.