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People with epilepsy (PWE), particularly those with more severe seizures, are at risk of premature death. The contribution of deaths unrelated to epilepsy to this risk is likely to be significant. Recent studies indicate that comorbid conditions are similarly increased in PWE. The reason for these increases in unrelated deaths and comorbid conditions is unclear. In this article, we argue that having seizures is psychologically stressful, and that this stress can lead to a whole range of pathophysiological changes that may trigger various physical illnesses. Hence, psychological stress may be a significant factor contributing to the increase in mortality and comorbidity rates in PWE. This speculation is unlikely to be proven at this stage because of the complexity of the trials required. In PWE who continue to have seizures, more needs to be done to help them cope with the stress. Additionally, attention needs to be paid to improve nutritional status and physical fitness. These steps are likely to enhance the overall health of PWE and may reduce premature mortality and comorbidity rates.