Nationwide monitoring of atmospheric mercury (Hg) deposition and Hg concentrations in fish has created the opportunity to analyze the causes and consequences of Hg contamination of fish across large regions of the United States. Here we present a case study of the south central United States where we have used datasets on Hg deposition (NADP), land cover (NLCD), and Hg concentrations in fish (USGS NDMMF) to analyze spatial patterns of methyl mercury (MeHg) contamination in fish and risk to human health.  In our case study, we estimated the MeHg concentrations of five sizes of a low trophic position fish (Bluegill, Lepomis macrochirus) and a high trophic position fish (Largemouth Bass, Micropterus salmoides) in 14 ecoregions of the south central United States. Within ecoregions, the average concentrations of MeHg in fish increased with Hg deposition adjusted for the presence of coniferous forest coverage, fish trophic position and fish size. Most sizes of Largemouth Bass, but not Bluegill, had average MeHg concentrations that would pose a risk to human health. These results have implications for the use of fish consumption advisories to inform the public about MeHg in recreationally-caught fish. Due to widespread atmospheric Hg deposition, all recreationally-caught fish are contaminated with MeHg and in cases where MeHg concentrations are elevated, their consumption poses a potential threat to human health. In the United States, informing the public about the potential health hazard of consuming recreationally-caught fish that are contaminated with MeHg is primarily the responsibility of the states, territories and tribes. These agencies monitor concentrations of MeHg in fish and issue consumption advisories if the concentrations are deemed to be hazardous to humans. However, the majority of water bodies are not monitored, which could create the false impression that fish from these un-monitored water bodies are safe even though there is no information about their MeHg contamination. The USGS has compiled data on MeHg concentrations in fish collected from fish monitoring programs across the United States and we suggest that this database be used to develop an ecoregion-based monitoring system of MeHg contamination in recreationally-caught fish.  The ecoregion-based monitoring system could be used to provide the public and regulators with estimates of MeHg concentrations in different species and sizes of recreationally-caught fish. This ecoregion-based monitoring approach could also be used to develop a new federally-managed fish consumption advisory system that would be complementary to current state fish consumption advisory systems.