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Although studies have documented increased mortality during heat waves, little information is available on the subgroups most susceptible to these effects. We evaluated the effects of summertime high temperature on daily mortality among population subgroups defined by demographic characteristics, socioeconomic status, and episodes of hospitalization for various conditions during the preceding 2 years.We studied a total of 205,019 residents of 4 Italian cities (Bologna, Milan, Rome, and Turin) age 35 or older who died during 1997–2003. The case-crossover design was applied to evaluate the association between mean apparent temperature (same and previous day) and all-cause mortality. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of dying at 30°C (apparent temperature) relative to 20°C were estimated accounting for time, population changes, and air pollution.We found an overall OR of 1.34 (CI = 1.27–1.42) at 30°C relative to 20°C. The odds ratio increased with age and was higher among women (OR = 1.45; 1.37–1.52) and among widows and widowers (1.50; 1.33–1.69). Low area-based income modestly increased the effect. Among the preexisting medical conditions investigated, effect modification was detected for previous psychiatric disorders (1.69; 1.39–2.07), depression (1.72; 1.24–2.39), heart conduction disorders (1.77; 1.38–2.27), and circulatory disorders of the brain (1.47; 1.34–1.62). Temperature-related mortality was higher among people residing in nursing homes, and a large effect was also detected for hospitalized subjects.Subsets of the population that are particularly vulnerable to high summer temperatures include the elderly, women, widows and widowers, those with selected medical conditions, and those staying in nursing homes and healthcare facilities.