Background: The Deepwater Horizon (DH) blowout resulted in fisheries closings across the Gulf of Mexico. Federal agencies, in collaboration with impacted Gulf states, developed a protocol to determine when it is safe to reopen fisheries based on sensory and chemical analyses of seafood. All federal waters have been reopened, yet concerns have been raised regarding the robustness of the protocol to identify all potential harmful exposures and protect the most sensitive populations.Objectives: We aimed to assess this protocol based on comparisons with previous oil spills, published testing results, and current knowledge regarding chemicals released during the DH oil spill. Methods: We performed a comprehensive review of relevant scientific journal articles and government documents concerning seafood contamination and oil spills and consulted with academic and government experts. Results: Protocols to evaluate seafood safety before reopening fisheries have relied on risk assessment of health impacts from polycyclic aromatic hydrocarbon (PAH) exposures, but metal contamination may also be a concern. Assumptions used to determine levels of concern (LOCs) after oil spills have not been consistent across risk assessments performed after oil spills. Chemical testing results after the DH oil spill suggest PAH levels are at or below levels reported after previous oil spills, and well below LOCs, even when more conservative parameters are used to estimate risk. Conclusions: We recommend use of a range of plausible risk parameters to set bounds around LOCs, comparisons of post-spill measurements with baseline levels, and the development and implementation of long-term monitoring strategies for metals as well as PAHs and dispersant components. In addition, the methods, results, and uncertainties associated with estimating seafood safety after oil spills should be communicated in a transparent and timely manner, and stakeholders should be actively involved in developing a long-term monitoring strategy.