Southern sea otters have been actively managed for their conservation and recovery since listing on the federal Endangered Species Act in 1977. Still, they remain constrained to a geographically small area on the central coast of California relative to their former coast-wide range, with population numbers far below those of the estimated optimal sustainable population size. Species managers have discussed reintroducing southern sea otters into parts of their historic range to facilitate sustained population growth and geographic range expansion. San Francisco Bay (SFB), historically home to several thousand sea otters, is one location identified as a candidate release site for these reintroductions. The return of sea otters to SFB could bring benefits to local ecosystem restoration and tourism, in addition to spurring sea otter population growth to meet recovery goals. However, this is a highly urbanized estuary, so sea otters could also be exposed to serious anthropogenic threats that would challenge a successful reintroduction. In light of these potential detriments we performed a spatially-explicit risk assessment to analyze the suitability of SFB for southern sea otter reintroduction. We looked at threats to sea otters specific to SFB, including: the impacts of vessel traffic from commercial shipping, high-speed ferries, and recreational vessels; environmental contaminants of methylmercury and polychlorinated biphenyls; major oil spills; and commercial fishing. Factors that influenced the relative threat imposed by each stressor included the spatio-temporal extent and intensity of the stressor and its mitigation potential. Our analysis revealed the complex spatial and temporal variation in risk distribution across the SFB. The type and magnitude of anthropogenic risk was not uniformly distributed across the study area. For example, the central SFB housed the greatest cumulative risk, where a high degree of vessel traffic and other stressors occurred in conjunction. The individual stressors that contributed to this risk score varied across different parts of the study area as well. Whereas vessel traffic, particularly of fast ferries, was a high scoring risk factor in in the north and central bay, in the south bay it was environmental contaminants that caused greater risk potential. To help identify areas within the study area that managers might want to target for release efforts, the spatially-explicit risk map revealed pockets of SFB that could provide both suitable habitat and relatively low overall risk. However in some cases these were adjacent or in close proximity to identified high-risk portions of habitat in SFB. This predictive suitability and risk assessment can be used by managers to consider the spatial distribution of potential threats, and risk abatement that may be necessary for sea otters to re-occupy their historic home range in SFB.