BACKGROUND: Stress is a consequence of different types of external demands, most of which have been shown to be associated with increased risk of ischaemic heart disease (IHD), but whether accumulation of stressors over a life-course results in additional risk of IHD remains unknown. This study investigates the impact of major life events (MLE) in childhood, adulthood and at work, singly and accumulated, on incident IHD in men and women and examines vital exhaustion (VE) and use of tranquillizers as potential mediators. Material and methods The study includes 8738 participants, 57% women, from the third wave of the Copenhagen City Heart Study, who in 1991-93 answered a range of questions on MLE, VE and use of tranquillizers. The participants were followed in a nationwide hospital discharge register until 2007. RESULTS: During follow-up, 653 experienced a first-time incident of IHD. In general, there were no associations between MLE and incidence of IHD. However, being placed in care during childhood was associated with a higher risk of IHD among women [hazard ratio (HR) = 1.36; 95% confidence interval (95% CI) 0.97-1.89], but a lower risk of IHD among men (HR¿=¿0.72; 95% CI 0.51-1.03). MLE showed a dose-response association with psychological risk factors with highest estimates for those exposed to MLE in all three life domains: VE [odds ratio (OR)¿=¿15.07; 95% CI 8.97-25.31] and use of tranquillizers (OR¿=¿4.41; 95% CI 3.10-6.26). CONCLUSION: This prospective study finds no associations between accumulated MLE and IHD. MLE is, however, strongly associated with VE and use of tranquillizers. The results underscore the problems in conceptualizing and measuring MLE.