Background: Exposure to second-hand smoke has been shown to be associated with increased cardiovascular mortality in several, but not all, epidemiologic studies. Our aim was to investigate the risk of circulatory death associated with exposure to second-hand smoke in never-smokers in a very large prospective study, the European Prospective Investigation into Cancer and Nutrition. A secondary aim was to use cotinine levels for cross-validating self-reported second-hand smoke exposure. Methods: Cox proportional hazard models were used to investigate the risk of death due to circulatory causes associated with second-hand smoke exposure in 135,233 never-smokers. Exposure to second-hand smoke was assessed through a questionnaire at enrollment and then validated against plasma cotinine measurements in a subsample. Results: Study participants who reported second-hand smoke exposure at home had higher cotinine levels (median plasma cotinine concentration in exposed = 0.82 μg/L; in those unexposed 0.02 μg/L). Second-hand smoke exposure at home was associated with an increased risk of dying from cardiovascular diseases (hazard ratio HR = 1.38 95% confidence interval = 1.01–1.90), all circulatory diseases (1.28 0.98–1.69), and coronary heart disease (1.31 0.83–2.08) after adjustment for age, sex, education, physical activity, and body mass index. Dose-response relationships were observed between exposure to second-hand smoke at home and risk of circulatory death (HR per each additional hour/d = 1.25 1.04–1.50). Having a partner who smokes more than 30 cigarettes per day considerably increased the risk of a circulatory death (2.94 1.11–7.78). Second-hand smoke exposure at home was not associated with total mortality (1.03 0.93–1.13). Discussion: Exposure to second-hand smoke at home (as confirmed by plasma cotinine levels) increases the risk of cardiovascular mortality.