Fisheries are human activities that alter resource availability for species in marine ecosystems. While fisheries remove fish biomass, they may also provide new feeding opportunities to various marine predators. These species, depredating on catches directly on the fishing gear, has emerged as major human-wildlife conflict with socio-economic and ecological impacts globally. This study investigated the extent of this conflict in multiple commercial Patagonian toothfish (Dissostichus eleginoides) fisheries across subantarctic waters where both killer whales (Orcinus orca) and sperm whales (Physeter macrocephalus) feed on toothfish caught on longline hooks. Using long-term datasets from Chile (South Pacific Ocean), the South West Atlantic, Prince Edward and Marion Islands, Crozet Islands, Kerguelen Islands, and Heard Island and McDonald Islands (Indian sector of the Southern Ocean) fisheries, statistical models were developed to predict and quantify the catch removals due to whale depredation interactions. The results indicated that these removals were large, totalling more than 6,600 t of toothfish between 2009 and 2016 with an overall annual mean of 837 t [95% CI 480-1,195 t], comprised of 317 t [232-403t ] and 518 t [247-790 t] removed by killer whales and sperm whales, respectively. Catch removals greatly varied between areas, with the largest estimates found at Crozet Islands, where on average 279 t [179-379 t] of toothfish was taken per year by killer and sperm whales between 2004 and 2018, equivalent to 30% [21-37%] of the total catches. Together, these findings provide metrics needed to assess the impacts of depredation interactions on the toothfish fishing industry, whale populations, fish stocks and associated ecosystems. Paired with increasing trends in depredation levels being detected in some areas, this study highlights the large scale significance of the depredation issue in subantarctic regions, where fisheries are the primary socio-economic activity operating in these ecosystems.