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The association between Creutzfeldt–Jakob disease (CJD) and stressful life events was examined in a pilot case–control study in Germany. The study sample consisted of 37 CJD cases and 37 controls, both groups were frequency-matched for age and sex. In standardised interviews of close relatives of the cases and the controls, all stressful life events were assessed and subsequently grouped into one of the following three subgroups: psychosocial stress events, medical operations with hospitalisation, and other serious medical examinations. A significantly higher proportion of CJD cases experienced stressful life events during the last six months before disease onset than controls (65% vs. 32%, p = 0.01), yielding an odds ratio (OR) of 3.85 (95% confidence interval (CI): 1.33–11.30). We found the clearest distinction between cases and controls for the subgroup of medical operations where an OR of 6.97 (95% CI: 0.76–329.20) was observed. Further data indicated that stressful events seem to influence not only the onset of CJD but also the progression of the disease. Although based on a rather small study sample, this pilot case–control investigation suggests evidence that stressful life events in the last six months before disease onset may influence CJD occurrence and may modify the course of disease. This ‘stress hypothesis’, which is in line with findings from other epidemiological and experimental studies in CJD, is thus a promising direction for future CJD research as it could enlighten the pathophysiological mechanisms and point towards strategies for the prevention and therapy of CJD.