Despite an increase in heat-related deaths occurring in England in recent years, one of the key recommended actions of identifying individuals at risk and deploying targeted interventions is not routinely undertaken. A major contributing factor to this is a lack of understanding of the individual-level risk factors that would support an evidence-based approach to targeted prevention. A time-stratified case-crossover analysis was undertaken of 37 individual-level clinical risk factors. Patient’s data were obtained from the Clinical Practice Research Datalink. Conditional logistic regression was used to characterise associations between temperature and the risk of death on hot days. Heat mortality risk was modified by a large range of pre-existing conditions, with cardiorespiratory, mental health and cognitive function conditions, diabetes and Parkinson’s, all increasing risk. The most striking increase was observed for depression with an OR of 1.25 (95% CI 1.09 to 1.44), the highest observed for pre-existing conditions. Individuals prescribed medications to treat heart failure and high blood pressure also have increased odds of death during heatwaves. There appears to be evidence of an increasing trend in ORs for diastolic blood pressure (DBP) categories, with ORs increasing from low DBP up to prehypertensive DBP group. This is the first study to explore a comprehensive set of individual-level clinical risk factors and heat using primary care records in England. Results presented have important implications for patient medication management during heat events, incorporating heat-risk considerations into other health policies such as suicide prevention plans and highlighted potential differences between clinical vulnerability and patients at risk.