Heat waves are extreme events characterized by sweltering weather over an extended period. Skillful projections of heat waves and their impacts on human mortality can help develop appropriate adaptation strategies. Here, we provide nuanced projections of heat wave characteristics and their effect on human mortality over the Eastern Mediterranean based on ERA5 reanalysis and CORDEX ensemble simulations. Heat waves were identified according to the 90th percentile threshold of the Climatic Stress Index (CSI), specifically tailored for the summer conditions in this region.We provide evidence that heat waves in the region are projected to occur seven times more often and last three times longer by the end of the 21st century (RCP8.5). We find that heat waves will become more persistent in a warmer world. Finally, we offer a conservative estimate of excess mortality in Israel based on a simple linear model. The projected changes in heat stress intensity and frequency may result in ~330 excess deaths per summer at the end of the 21st century (RCP8.5) compared to the historical baseline of ~30 heat-related deaths, particularly pronounced in the elderly (65+ years).We conclude that heat waves increasingly threaten society in the vulnerable Eastern Mediterranean. We also emphasize that true interdisciplinary regional collaborations are required to achieve adequate public health adaptation to extreme weather events in a changing climate.