There is presently debate over the degree to which the fishery for Antarctic toothfish (Dissostichus mawsoni; ‘toothfish’) in the Ross Sea may affect the ecological viability of top predators such as Weddell seals (Leptonychotes weddellii), but available evidence remains inconclusive as a result of both methodological limitations and knowledge gaps. We present new stable isotope data on Weddell seal prey, consider the assumptions underlying application of stable isotope methodology to Weddell seals, and estimate the potential contribution of toothfish to the diet of Weddell seals using an isotope mixing model. As a new approach, we also estimate Weddell seal food requirements by considering nutritional quality of potential prey species including toothfish in the context of updated estimates of Weddell seal energy requirements. The energy density of potential prey items (fish and invertebrates) covers a four-fold range. Nutritional analysis of Ross Sea prey suggests that toothfish may represent a unique high-energy food resource for Weddell seals that possibly cannot be adequately replaced by other prey, in particular during periods of high energy demand such as late-stage lactation and the post-breeding recovery of body weight and condition. The assumed dominance of Antarctic silverfish (Pleuragramma antarcticum) in Weddell seal diets should be re-examined given the known biases of methods used to derive diet estimates. While large (>30 g) silverfish occurring at high densities are a valuable nutritional resource, smaller size classes are unlikely to be adequate to meet the estimated energy requirements of adult Weddell seals. Our ability to conclusively determine possible dependence of Weddell seal populations on toothfish, and hence possible impacts of toothfish removal by fisheries, is primarily hindered by (a) insufficient information on Weddell seal diet, due to inadequate temporal coverage and biased methodology, and (b) uncertainty regarding Weddell seal abundance and spatial foraging patterns in the Ross Sea region.