The risk associated with any climate change impact reflects intensity of natural hazard and level of human vulnerability. Previous work has shown that a wet-bulb temperature of 35°C can be considered an upper limit on human survivability. On the basis of an ensemble of high-resolution climate change simulations, we project that extremes of wet-bulb temperature in South Asia are likely to approach and, in a few locations, exceed this critical threshold by the late 21st century under the business-as-usual scenario of future greenhouse gas emissions. The most intense hazard from extreme future heat waves is concentrated around densely populated agricultural regions of the Ganges and Indus river basins. Climate change, without mitigation, presents a serious and unique risk in South Asia, a region inhabited by about one-fifth of the global human population, due to an unprecedented combination of severe natural hazard and acute vulnerability.