Heat is the leading cause of weather-related deaths in the United States, responsible for more than 3,400 fatalities between 1999 and 2003. As climate change is projected to raise average mean temperatures over North America by approximately 6.3°-11°F within this century, heatwaves are likely to increase in magnitude and duration in portions of the U.S. where they already occur. This analysis attempts to quantify the projected increase in heat-related mortality due to climate change for 21 U.S. cities by determining the sensitivity of the population of each city to extreme heat events and applying that sensitivity to a projection of mid-century climate conditions. A method to account for acclimatization was also employed, as it is likely that the population will partially adjust to the increased warmth. The findings indicate that for most of the cities studied, climate change is projected to more than double the average number of summertime heat-related deaths, with the greatest increases occurring in mid-latitude major cities where summer climate variability is greatest.