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The CYBA gene encodes the regulatory subunit of NADPH oxidase, which maintains the redox state within cells and in the blood vessels. That led us to investigate the course of coronary artery disease (CAD) with regards to CYBA polymorphisms. Thus, we recruited 1197 subjects with coronary atherosclerosis and observed them during 7-year follow-up. Three CYBA polymorphisms: c.214C>T (rs4673), c.-932G>A (rs9932581), and c.*24G>A (1049255) were studied for an association with death, major adverse cardiovascular events (MACE) and an elective percutaneous coronary intervention or coronary artery bypass grafting (PCI/CABG). We found an association between the CYBA c.214C>T polymorphism and two end points: death and PCI/CABG. CYBA c.214TT genotype was associated with a lower risk of death than C allele (9.5% vs. 21%, p < 0.05) and a higher risk of PCI/CABG than C allele (69.3% vs. 51.7%, p < 0.01). This suggests that the CYBA c.214TT genotype may be a protective factor against death OR = 0.47 (95%CI 0.28–0.82; p < 0.01), while also being a risk factor for an elective PCI/CABG OR = 2.36 (95%CI 1.15–4.82; p < 0.05). Thus, we hypothesize that among patients with coronary atherosclerosis, the CYBA c.214TT genotype contributes to atherosclerotic plaque stability by altering the course of CAD towards chronic coronary syndrome, thereby lowering the incidence of fatal CAD-related events. [ABSTRACT FROM AUTHOR]