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The sea urchin Diadema setosum is an ecological key species across its range, particularly on coral reefs. In 2006 D. setosum was first observed in the Mediterranean Sea, and since, it has proliferated to occupy the entire Levantine Basin. Here we report the mass mortality of the invasive D. setosum in the Mediterranean Sea. This is the first report of D. setosum mass mortality. The mortality spans over 1000 km along the Levantine coast of Greece and Turkey. The current mortality shows similar pathologies to previously reported Diadema mass mortality events, suggesting pathogenic infection as the cause of mortalities. Maritime transport, local currents, and fish predation of infected individuals may distribute pathogens at varying geographical scales. Due to the proximity of the Levantine Basin to the Red Sea, the risk of pathogen transport to the native Red Sea D. setosum population is imminent—with potentially catastrophic consequences.