BACKGROUND: We investigated whether circulating angiotensinogen levels are associated with the risk of ischemic stroke and examined sex-specific differences. METHODS: We included 5622 participants (mean age, 62.7 years; 52% women) free of cardiovascular disease at baseline (2000-2002) and followed them through 2020. Cox models assessed the association between angiotensinogen and ischemic stroke, including sex-stratified hazard ratios (HRs) with 95% CIs. Mediation analyses estimated the contribution of risk factors to observed associations. Subgroup analyses with multiplicative interaction testing were conducted. RESULTS: During follow-up, 283 ischemic stroke events occurred. Each 1-SD increase in log-transformed angiotensinogen was associated with a 16% higher stroke risk (HR, 1.16 [95% CI, 1.00-1.34]). Significant interaction with sex was observed (P interaction<0.001). In men, angiotensinogen showed a positive dose-response association with ischemic stroke (adjusted HR per SD increase, 1.71 [95% CI, 1.33-2.19]). Compared with the lowest tertile (<16.8 μg/mL), adjusted HRs were 1.68 (95% CI, 1.08-2.61) and 1.95 (95% CI, 1.26-3.03) for the second and third (>20 μg/mL) tertiles, respectively (P trend=0.004). Diabetes marginally mediated the association in men (proportion mediated, 0.04 [95% CI, 0.00-0.15]). Significant evidence of an association between angiotensinogen and ischemic stroke in women was not observed (HR, 1.07 [95% CI, 0.88-1.29] per SD). No significant multiplicative interactions were observed across subgroups defined by age, race, smoking status, diabetes, obesity, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use, hypertension, chronic kidney disease, and high-sensitivity C-reactive protein levels in either sex after Bonferroni correction (all P interaction>0.002). CONCLUSIONS: Higher circulating angiotensinogen levels are associated with an increased risk of ischemic stroke in men, independent of blood pressure.