The association between personality traits and mortality might differ as a function of socioeconomic status (SES). Our aim was to evaluate the all-cause, cardiovascular disease (CVD), and cancer mortality risk associated with neuroticism or extraversion and their interactions with SES in a representative sample of the UK adult population. A total of 5450 participants (2505 men) from the Health and Lifestyle Survey completed the Eysenck Personality Inventory at baseline and were monitored for vital status over 25 years. SES was defined as a latent variable comprising occupational social class, educational attainment, and income. A significant neuroticism-by-SES-by-sex interaction (p = .04) for CVD mortality revealed a neuroticism-by-SES interaction specific to women. Compared to women with average SES, those with both high neuroticism and low SES were at an increased risk for CVD mortality (hazard ratio = 2.02, 95% confidence interval = 1.45-2.80), whereas those with high neuroticism and high SES combined were at a decreased risk for CVD mortality (hazard ratio = 0.61, 95% confidence interval = 0.38-0.97, p for interaction = 0.003). The interaction term was not explained by health behaviors (10% attenuation) and physiological variables (11% attenuation). This interaction was not observed for all-cause and cancer mortality risks or among men for CVD mortality. High neuroticism is a risk factor for cardiovascular mortality in women with low SES, whereas in women with higher SES, it is protective. Further research is needed to replicate this finding and identify the mechanisms behind the modifying effect of SES on neuroticism.