Oxidative stress plays a central role in atherosclerosis, yet prospective population-based evidence linking specific enzymatic sources of reactive oxygen species to cardiovascular disease (CVD) is limited. NADPH oxidase 2 (NOX2) is a major source of vascular oxidative stress, but its prognostic value in the general population remains unclear. We conducted a case-cohort study nested within the Moli-sani prospective cohort, including a random subcohort of 1648 participants and 1283 incident CVD cases. Baseline serum NOX2-derived peptide (sNOX2-dp) levels were measured by ELISA. Associations with incident CVD were evaluated using Cox models adapted for the case-cohort design, with adjustment for major cardiovascular risk factors. Dose-response relationships were assessed using restricted cubic splines, and additional analyses examined whether adjustment for markers of low-grade systemic inflammation attenuated the association. Higher circulating NOX2 levels were associated with increased CVD risk after adjustment for major cardiovascular risk factors. Compared with the lowest quintile, risk estimates increased across NOX2 quintiles, reaching an HR of 1.70 in Q5 (P for trend = 0.0033). Additional adjustment for the INFLA-Score or C-reactive protein did not materially attenuate the association. In a large population-based cohort, elevated circulating NOX2 was associated with incident cardiovascular events after adjustment for traditional risk factors. The association was not materially attenuated by additional adjustment for the inflammatory markers measured in this study, supporting the potential value of NOX2-related oxidative stress as a marker of cardiovascular risk.