AIMS: Many patients are afraid of dying during acute coronary syndrome (ACS), but the origins and biological correlates of these emotional responses are poorly understood. This study evaluated the prevalence of fear of dying, associations with inflammatory responses during ACS, and later heart rate variability (HRV) and cortisol secretion. METHODS AND RESULTS: Two hundred and eight patients admitted with clinically verified ACS rated their fear of dying on interview in hospital. Plasma tumour necrosis factor (TNF)alpha was recorded on admission, and HRV and salivary cortisol were assessed 3 weeks later. Intense distress and fear of dying was experienced by 21.7%, with moderate levels in 66.1% patients. Fear of dying was more common in younger, lower socioeconomic status, and unmarried patients. It was positively associated with plasma TNFalpha on admission after controlling for sociodemographic factors, clinical risk, and pain intensity (adjusted odds = 4.67, 95% C.I. 1.66-12.65). TNFalpha was associated with reduced HRV 3 weeks later, adjusting for clinical and sociodemographic factors and medication (P = 0.019), while fear of dying was associated with reduced cortisol output (P = 0.004). CONCLUSIONS: Intense distress and fear of dying and heightened inflammation may be related manifestations of an acute biobehavioural response to severe cardiac injury, and have implications for prognostically significant biological risk processes.