Introduction: Moderate stroke patients with National Institutes of Health Stroke Scale (NIHSS) scores of 4–10 and without intravenous thrombolysis or endovascular treatment are basically excluded from current secondary prevention trials. We aimed to explore the effectiveness of mono- versus dual-antiplatelet treatment (DAPT) strategies against subsequent stroke for these patients in a nationwide cohort. Methods: Data were derived from the Third China National Stroke Registry (CNSR-III). In this prospective nationwide cohort, moderate ischemic stroke patients with NIHSS scores of 4–10 and without intravenous thrombolysis or endovascular treatment were included and categorized into mono- or dual-antiplatelet groups. Demographics, medical history, NIHSS score, imaging, and laboratory data were collected. The outcomes were stroke recurrence and all-cause mortality at 3 months and 1 year, respectively. Cox proportional hazards models were utilized to investigate the association of treatment strategies and prognosis. Results: Of a total of 2,414 patients enrolled in the study, 1,633 (67.6%) received clopidogrel or aspirin, and 781 (32.4%) received DAPT. Recurrent stroke occurred in 108 (6.6%) patients of the mono-antiplatelet group and 40 (5.1%) patients of the DAPT group (adjusted hazard ratio [aHR] 0.73, 95% confidential interval [CI] 0.47–1.13, p = 0.16) at 3 months, and the rate of stroke recurrence was 10.7% in the mono-antiplatelet group and 8.6% in the DAPT group (aHR 0.81, 95% CI 0.58–1.13, p = 0.22) at 12 months. The DAPT paradigm was not significantly associated with death at 3 months (0.6% vs. 0.3%, aHR 0.28, 95% CI: 0.04–2.25) but significantly reduced the mortality at 12 months (2.3% vs. 1.0%, aHR 0.41, 95% CI: 0.17–0.98, p = 0.046). Conclusions: In moderate stroke patients presenting within 24 h of symptom onset, the addition of clopidogrel 75 mg to aspirin might not be associated with lower risk of recurrent stroke than aspirin or clopidogrel alone.

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