The MIT Integrated Global System Model (IGSM) framework, extended to include a Water Resource System (WRS) component, is applied to an integrated assessment of effects of alternative climate policy scenarios on U.S. water systems. Climate results are downscaled to yield estimates of surface runoff at 99 river basins of the continental U.S., with an exploration of climate patterns that are relatively wet and dry over the region. These estimates are combined with estimated groundwater supplies. An 11-region economic model (USREP) sets conditions driving water requirements estimated for five use sectors, with detailed sub-models employed for analysis of irrigation and electric power. The water system of the interconnected basins is operated to minimize water stress. Results suggest that, with or without climate change, U.S. average annual water stress is expected to increase over the period 2041 to 2050, primarily because of an increase in water requirements, with the largest water stresses projected in the South West. Policy to lower atmospheric greenhouse gas concentrations has a beneficial effect, reducing water stress intensity and variability in the concerned basins.