Mercury and PCBs are used by non-governmental organizations and federal agencies to inform seafood safety recommendations. Pollution dynamics suggest recommendations on the national scale may be too large to be accurate. We tested softshell and hardshell blue crab, white and pink shrimp, oysters, clams, spot, and mullet from fishers in each of the three North Carolina fishery districts. We measured mercury using EPA method 7473 and PCBs using a commercially available ELISA kit. Over 97% of samples were below the Environmental Protection Agency levels of concern for both mercury and PCBs. Mercury and PCBs have different spatial dynamics, but both differ significantly by water body, suggesting that seafood safety recommendations should occur by water body instead of at the national scale. This finding supports previous research suggesting that differences in water chemistry, terrestrial influence, and flushing time in a particular water body control the contaminant load in locally resident species.