We report national scale estimates of CO2 emissions from fossil-fuel combustion and cement production in the United States based directly on atmospheric observations, using a dual-tracer inverse modeling framework and CO2 and measurements obtained primarily from the North American portion of the National Oceanic and Atmospheric Administration’s Global Greenhouse Gas Reference Network. The derived US national total for 2010 is 1,653 ± 30 TgC yr−1 with an uncertainty () that takes into account random errors associated with atmospheric transport, atmospheric measurements, and specified prior CO2 and 14C fluxes. The atmosphere-derived estimate is significantly larger () than US national emissions for 2010 from three global inventories widely used for CO2 accounting, even after adjustments for emissions that might be sensed by the atmospheric network, but which are not included in inventory totals. It is also larger () than a similarly adjusted total from the US Environmental Protection Agency (EPA), but overlaps EPA’s reported upper 95% confidence limit. In contrast, the atmosphere-derived estimate is within of the adjusted 2010 annual total and nine of 12 adjusted monthly totals aggregated from the latest version of the high-resolution, US-specific “Vulcan” emission data product. Derived emissions appear to be robust to a range of assumed prior emissions and other parameters of the inversion framework. While we cannot rule out a possible bias from assumed prior Net Ecosystem Exchange over North America, we show that this can be overcome with additional measurements. These results indicate the strong potential for quantification of US emissions and their multiyear trends from atmospheric observations.