Background and aims: Various bio-psychological mechanisms underlying the association between mental health problems and metabolic syndrome remain unknown. We investigated the role of irrational beliefs in conjunction with anxiety, depression and hostility in the 10-year metabolic syndrome (MetS) incidence, and the effect of biochemical and socio-behavioral factors on the aforementioned associations. Methods and results: ATTICA is a prospective, cohort study (2002–2012). The sample included 591 participants [51.3% men (aged 41.5 ± 10 years) and 48.7% women (aged 37.5 ± 11.5 years)], free of MetS at baseline. Detailed biochemical, clinical, and lifestyle evaluations were performed, while participants’ irrational beliefs, anxiety, depression and hostility were assessed using the Irrational Beliefs Inventory, the Spielberger State-Trait Anxiety Inventory, the Zung Self-Rating Depression Scale and the Hostility and Direction of Hostility Questionnaire, respectively. Multiple logistic regression was applied to estimate the odds ratio (OR) of developing MetS and to control for confounders, as well as stratified logistic regression to detect moderator effects. High irrational beliefs were associated with 1.5-times higher odds of developing MetS than low irrational beliefs. Especially, participants with high irrational beliefs and high anxiety were 96% more likely to develop MetS, compared with those with low irrational beliefs and low or high anxiety (OR = 1.96; 95% CI = 1.01, 3.80). Conclusion: The findings of the study underline the important role of irrational beliefs and anxiety in the development of MetS and the need to build new holistic approaches focused on the primary prevention of both mental health and MetS.