Oxidative stress contributes to endothelial dysfunction and is involved in the pathogenesis of myocardial infarction (MI) and stroke. However, associations of biomarkers of oxidative stress with MI and stroke have not yet been addressed in large cohort studies. A nested case-control design was applied in four population-based cohort studies from Germany, Czech Republic, Poland and Lithuania. Derivatives of reactive oxygen metabolites (d-ROMs) levels, as a proxy for the reactive oxygen species burden, and total thiol levels (TTL), as a proxy for the reductive capacity, were measured in baseline serum samples of 476 incident MI cases and 454 incident stroke cases as well as five controls per case individually matched by study center, age and sex. Statistical analyses were conducted with multi-variable adjusted conditional logistic regression models. d-ROMs levels were associated with both MI (odds ratio (OR), 1.21 [95% confidence interval (CI) 1.05-1.40] for 100 Carr units increase) and stroke (OR, 1.17 [95% CI 1.01-1.35] for 100 Carr units increase). TTL were only associated with stroke incidence (OR, 0.79 [95% CI 0.63-0.99] for quartiles 2-4 vs. quartile 1). The observed relationships were stronger with fatal than with non-fatal endpoints; association of TTL with fatal MI was statistically significant (OR, 0.69 [95% CI 0.51-0.93] for 100 μmol/L-increase). This pooled analysis of four large population-based cohorts suggests an important contribution of an imbalanced redox system to the etiology of mainly fatal MI and stroke events.