This report evaluates the potential impacts of large-scale mining development on salmon and other fish populations, wildlife, and Alaska Native cultures in the Nushagak River and Kvichak River watersheds of Bristol Bay, Alaska. It is not an assessment of a specific mine proposal for development, nor does it outline decisions made or to be made by the U.S. Environmental Protection Agency (USEPA). The assessment was conducted as an ecological risk assessment and starts with a review and characterization of the fisheries, wildlife, and Alaska Native cultures of the Bristol Bay watershed, particularly the Nushagak and Kvichak River watersheds. We developed realistic mine scenarios that include an open pit mine producing 0.25, 2.0, and 6.5 billion tons of ore and a 138-km transportation corridor. Based on these mine scenarios, we conclude that mining would, at minimum, cause the loss of spawning and rearing habitat for multiple salmonids (Pacific salmon, rainbow trout, and Dolly Varden). The mine footprint in each of the three scenarios would likely result in the direct loss of 38, 90, and 145 km of streams and 5.0, 12.4 and 19.4 km2 of wetlands, respectively. Water withdrawals for mine operations would significantly diminish habitat quality in an additional 15, 26 and 54 km of streams. Leakage of tailings and waste rock leachates during routine operations would result in instream copper levels sufficient to cause direct effects on salmonids in 29 and 57 km of streams beyond the mine footprint in the 2.0- and 6.5-billion-ton scenarios unless additional mitigation measures were taken. These leakages would not be likely to cause direct effects in streams under the 0.25-billion-ton scenario. Under a reasonable upper bound failure scenario for the wastewater treatment plant, copper concentrations would be sufficient to cause direct effects on salmonid fish in 45, 100, and 100 km of streams, respectively, under each mine scenario. The transportation corridor would cross 53 streams and rivers known or likely to support migrating and/or resident salmonids. At those road crossings, culvert failures could inhibit fish migration and degrade habitat, truck accidents could spill industrial chemicals, and runoff could reduce water quality. Failure of a tailings dam has a very low probability of occurrence, but a spill of 20% of the tailings from a single tailings storage facility would destroy more than 30 stream km, and more streams and rivers would have greatly degraded habitat for decades. A spill of product concentrate slurry along the transportation corridor would result in toxicity to fish in streams between the road and Iliamna Lake. Reductions in the populations of salmon would be expected from these habitat losses and toxic effects, but cannot be quantified. These losses would adversely affect the Alaska Native cultures and the wildlife of the region. The Nushagak River and Kvichak River watersheds contain multiple sites under consideration for large-scale mining. Potential risks of mining development on salmon and other fish populations are likely to increase as a result of the cumulative impacts of multiple mines.