The Mediterranean Sea is one of the most polluted marine basins and currently serves as a hotspot for marine litter. The seafloor represents the ultimate sink for most litter worldwide. Nevertheless, the knowledge about litter distribution and its interactions with benthic organisms in deep water is poorly understood. In 2018, we investigated spatial patterns of macro- and micro-litter distribution, and their effects on benthic communities in the Ligurian Sea. An oceanographic survey was carried out with a remotely operated vehicle and a multibeam echosounder on seven seamounts and canyons, at depths ranging from 350 to 2200 m. High litter accumulations were discovered at the mouth of the Monaco canyon, where estimated densities of up to 3.8 × 104 items km-2 were found at 2200 m depth. The highest abundance of urban litter items was found on the soft substrate, at the bottom of the deeper parts of the submarine canyons, which seem to act as conduits carrying litter from the shelf towards deeper areas. In contrast, fishing-related items were most abundant in the upper layer of the seamounts (300–600 m depths). Furthermore, more than 10% of the observed deep gorgonian colonies were entangled by lost longlines, indicating the detrimental effects of this fishing gear on benthic habitats. The discovery of new litter hotspots and the evaluation of how deep-sea species interact with litter contribute to increasing the knowledge about litter distribution and its effects on the deep ecosystem of the Mediterranean basin. All the observations recorded in this study showed substantial and irreversible changes in the deep and remote areas of marine environments, and these changes were found to be caused by humans. Our findings further stress the need for urgent and specific measures for the management of deep-sea pollution and the reduction of litter inputs in the environment.