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Extremes of temperature have been associated with short-term increases in daily mortality. We identified subpopulations with increased susceptibility to dying during temperature extremes, based on personal demographics, small-area characteristics, and preexisting medical conditions.We examined Medicare participants in 135 US cities and identified preexisting conditions based on hospitalization records before their deaths, from 1985 to 2006. Personal characteristics were obtained from the Medicare records, and area characteristics were assigned based on zip code of residence. We conducted a case-only analysis of over 11 million deaths and evaluated modification of the risk of dying associated with extremely hot days and extremely cold days, continuous temperatures, and water vapor pressure. Modifiers included preexisting conditions, personal characteristics, zip code–level population characteristics, and land cover characteristics. For each effect modifier, a city-specific logistic regression model was fitted and then an overall national estimate was calculated using meta-analysis.People with certain preexisting conditions were more susceptible to extreme heat, with an additional 6% (95% confidence interval = 4%–8%) increase in the risk of dying on an extremely hot day in subjects with previous admission for atrial fibrillation, an additional 8% (4%–12%) in subjects with Alzheimer disease, and an additional 6% (3%–9%) in subjects with dementia. Zip code level and personal characteristics were also associated with increased susceptibility to temperature.We identified several subgroups of the population who are particularly susceptible to temperature extremes, including persons with atrial fibrillation.