Background: Several studies have identified strong effects of high temperatures on mortality at population level; however, individual vulnerability factors associated with heat-related in-hospital mortality are largely unknown. The objective of the study was to evaluate heat-related in-hospital mortality using a multi-city case-crossover analysis. Methods: We studied residents of four Italian cities, aged 65+ years, who died during 1997Ð2004. For 94_944 individuals who died in hospital and were hospitalised two or more days before death, demographics, chronic conditions, primary diagnoses of last event and hospital wards were considered. A city-specific case-crossover analysis was performed to evaluate the association between apparent temperature and mortality. Pooled odds ratios (OR) of dying on a day with a temperature of 30¡C compared to a day with a temperature of 20¡C were estimated with a random-effects meta-analysis. Results: We estimated an overall OR of 1.32 (95% confidence interval: 1.25, 1.39). Age, marital status and hospital ward were important risk indicators. Patients in general medicine were at higher risk than those in high and intensive care units. A history of psychiatric disorders and cerebrovascular diseases gave a higher vulnerability. Mortality was greater among patients hospitalised for heart failure, stroke and chronic pulmonary diseases. Conclusions: In-hospital mortality is strongly associated with high temperatures. A comfortable temperature in hospitals and increased attention to vulnerable patients during heatwaves, especially in general medicine, are necessary preventive measures.