This study tested the hypothesis that a personality disposition defined by a strong sense of coherence is associated with a reduced risk of mortality. The authors prospectively examined, for ≤6 years, the relation between a strong sense of coherence and mortality due to all causes, cardiovascular disease, and cancer among 20,579 participants aged 41–80 years from the European Prospective Investigation into Cancer (EPIC)-Norfolk Study in the United Kingdom. Data were collected in 1996–2002. Participants were recruited by post from general practice age-sex registers and subsequently completed a postal assessment of their sense of coherence. During follow-up, 1,024 deaths were recorded. A strong sense of coherence was associated with a 30% reduction in mortality from all causes (rate ratio = 0.69, p < 0.0001), cardiovascular disease (rate ratio = 0.70, p = 0.001), and cancer (rate ratio = 0.74, p = 0.003), independent of age, sex, and prevalent chronic disease. These associations were consistent by sex, except that no association was observed for cancer mortality in women. The association for all-cause mortality remained after adjustment for cigarette smoking history, social class, body mass index, systolic blood pressure, cholesterol, hostility, and neuroticism (rate ratio = 0.76, p = 0.002). Results suggest that a strong sense of coherence may confer some resilience to the risk of chronic disease.