Background: Irrational beliefs, maladaptive emotions, and unhealthy lifestyle behaviors can adversely affect health status. However, limited research has examined the association between irrational beliefs and cardiovascular disease (CVD). The aim of this study was to evaluate the association between irrational beliefs and the 10-year CVD incidence among apparently healthy adults, considering the potential moderating or mediating role of particular social and lifestyle factors. Methods: The ATTICA study is a population-based, prospective cohort (2002–2012), in which 853 participants without a history of CVD [453 men (aged 45 ± 13 years) and 400 women (aged 44 ± 18 years)] underwent psychological evaluations. Among other tools, participants completed the irrational beliefs inventory (IBI, range 0–88), a self-reported measure consistent with the Ellis model of psychological disturbance. Demographic characteristics, detailed medical history, dietary, and other lifestyle habits were also evaluated. Incidence of CVD (i.e., coronary heart disease, acute coronary syndromes, stroke, or other CVD) was defined according to the International Coding Diseases (ICD)-10 criteria. Results: Mean IBI score was 53 ± 2 in men and 53 ± 3 in women (p = 0.88). IBI score was positively associated with 10-year CVD risk (hazard ratio 1.07, 95%CI 1.04, 1.13), in both men and women, and more prominently among those with less healthy dietary habits and lower education status; specifically, higher educational status leads to lower IBI score, and in conjunction they lead to lower 10-year CVD risk (HR for interaction 0.98, 95%CI 0.97, 0.99). Conclusions: The findings of this study underline the need to build new, holistic approaches in order to better understand the inter-relationships between irrational beliefs, lifestyle behaviors, social determinants, and CVD risk in individuals.