Reference points can help implement an ecosystem approach to fisheries management (EAF), by establishing precautionary removal limits for nontarget species and target species of ecological importance. PBR (Potential Biological Removal), developed under the U.S. Marine Mammal Protection Act (MMPA), is a limit for direct mortality for marine mammals, but it does not account for indirect effects of fishing due to prey depletion. I propose a generalization of PBR (called PBR*) to account for plausible changes in marine mammal carrying capacity (ΔK) from prey biomass decline relative to two example benchmarks: SSBMSY (maximum sustainable yield biomass for all known prey species) or SSBK (unfished prey biomass). PBR* can help identify when indirect fishing effects (alone, or combination with direct mortality estimates) may stymie MMPA objectives, and could inform catch limit estimates for target species that are also important as marine mammal prey. As a case study, I applied PBR* estimates to evaluate the possible combined direct + indirect effects of fishing on cetaceans in northeastern U.S. waters. Estimated distributions for ΔK were based on fish stock assessments and meta-analysis of predator-prey relationships from the mammalian literature. Based on this analysis, increased risk of marine mammal depletion due to indirect fishing effects was not evident, although this result must be interpreted cautiously given our limited understanding of cetacean diets and marine trophic dynamics. This study is intended to illustrate a possible practical approach for incorporating indirect fisheries impacts on marine mammals into a comprehensive management framework, and it raises several scientific and policy issues that merit further investigation.