OBJECTIVES: Several observational studies have suggested an association between high temperatures and all-cause mortality. However, estimates on more specific mortality outcomes are sparse, and frequently assessed in studies using different analytical methods. METHODS: A time series analysis was performed on 10 regions in England and Wales during the summers (June-September) of 1993-2006. Average percentage linear increases in risk for a 1°C increase in temperature above region-specific thresholds and attributable deaths were computed by cause-specific mortality and age groups (0-64, 65-74, 75-84, 85+). RESULTS: There was evidence of increased mortality with heat for almost all cause-of-death groups examined, with an overall increase in all-cause mortality of 2.1% (95% CI 1.6% to 2.6%) for a 1°C rise above the regional heat threshold. Among main causes, the steepest increase in risk was for respiratory mortality (+4.1% (3.5% to 4.8%) per 1°C). It was much smaller for cardiovascular causes (+1.8% (1.2% to 2.5%)) and myocardial infarction (+1.1% (0.7% to 1.5%)), but comparatively high for arrhythmias (+5.0% (3.2% to 6.9%)) and pulmonary heart disease (+8.3% (2.7% to 14.3%)). Among non- cardiorespiratory causes, the strongest effects were for genitourinary (+3.8% (2.9% to 4.7%)) and nervous system (+4.6% (3.7% to 5.4%)) disorders. 33.9% of heat deaths were attributable to cardiovascular causes, 24.7% to respiratory causes and 41.3% to all other causes combined. CONCLUSIONS: These results suggest that the risk of heat-related mortality is distributed across a wide range of different causes, and that targeting of preventative actions based on pre-existing disease is unlikely to be efficient.