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Assessing and managing cumulative impacts produced by interactive anthropogenic and natural drivers is a major challenge to achieve the sustainable use of marine spaces in line with the objectives of relevant EU acquis. However, the complexity of the marine environment and the uncertainty linked to future climate and socioeconomic scenarios, represent major obstacles for understanding the multiplicity of impacts on the marine ecosystems and to identify appropriate management strategies to be implemented. Going beyond the traditional additive approach for cumulative impact appraisal, the Cumulative Impact Index (CI-Index) proposed in this paper applies advanced Multi-Criteria Decision Analysis techniques to spatially model relationships between interactive climate and anthropogenic pressures, the environmental exposure and vulnerability patterns and the potential cumulative impacts for the marine ecosystems at risk. The assessment was performed based on spatial data characterizing location and vulnerability of 5 relevant marine targets (e.g. seagrasses and coral beds), and the distribution of 17 human activities (e.g. trawling, maritime traffic) during a reference scenario 2000-2015. Moreover, projections for selected physical and biogeochemical parameters (temperature and chlorophyll 'a') for the 2035-2050 timeframe under RCP8.5 scenario, were integrated in the assessment to evaluate index variations due to changing climate conditions. The application of the CI-Index in the Adriatic Sea, showed higher cumulative impacts in the Northern part of the basin and along the Italian continental shelf, where the high concentration of human activities, the seawater temperature conditions and the presence of vulnerable benthic habitats, contribute to increase the overall impact estimate. Moreover, the CI-Index allowed understanding which are the phenomena contributing to synergic pressures creating potential pathways of environmental disturbance for marine ecosystems. Finally, the application in the Adriatic case showed how the output of the CI-Index can provide support to evaluate multi-risk scenarios and to drive sustainable maritime spatial planning and management. (C) 2019 Elsevier B.V. All rights reserved.