Black individuals have a higher incidence of ischemic stroke (IS) than White individuals. The platelet receptor PAR4 harbors a functional dimorphism: rs773902 A/G (encoding Thr120/Ala120, respectively), and the A allele is associated with greater ex vivo platelet aggregation. The A allele frequency is 0.6 in Black individuals and 0.2 in White subjects. However, it is unknown whether the A allele contributes to racial differences in IS. In a prospective cohort, the REGARDS study, a Black subject-only analysis of 487 IS cases and 7,133 controls was performed, examining if the A allele was a risk for incident IS and worse IS outcome. We used Cox proportional hazards models to calculate hazard ratios (HR) with 95% confidence intervals (CI) of incident IS for the rs773902 A allele. Models were adjusted for age, sex, the first 5 genetic principal components, smoking, hypertension and diabetes. To directly test the effect of this PAR4 variant on IS, we generated the first humanized PAR4 (hPAR4) mouse strains expressing either hPAR4 Thr120 or hPAR4 Ala120. In REGARDS, the A allele was a risk factor for incident IS (HR 1.24; CI 1.04-1.53, p=0.046) and worse IS outcome (HR 2.04; CI 1.10-3.79, p=0.025). In a murine stroke model, hPAR4 Thr120 mice had worse stroke outcomes compared to hPAR4 Ala120 mice (60% increase, p=0.001). This phenotype was mediated, in part, by enhanced platelet activation (p=0.002), platelet-neutrophil interactions (p=0.014), and neutrophil extracellular traps (p=0.001). Direct inhibition of PAR4 with BMS-986120 was equally effective in improving stroke outcomes in hPAR4 Ala120 and Thr120 mice. In contrast, ticagrelor treatment improved stroke outcomes in hPAR4 Ala120 mice (50% decrease, p=0.007), but was ineffective in hPAR4 Thr120 mice, even when combined with aspirin. Importantly, blocking platelet-neutrophil interactions downstream of PAR4 with a murine analog of the FDA-approved P-selectin inhibitor crizanlizumab improved stroke outcomes in hPAR4 Thr120 mice (55% decrease, p=0.004). These results support a causal role for PAR4 Thr120 in IS that may explain part of the racial disparity in stroke. Our findings further suggest that different anti-platelet therapies may be needed for patients expressing PAR4 Thr120.