Thrombolysis treatment for patients with mild stroke is controversial. The aim of our study was to investigate whether patients with mild stroke or its specific etiologic subtype might benefit from rt-PA therapy. Data were derived from two cohorts of patients with and without rt-PA treatment: (1) the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) and (2) the China National Stroke Registry (CNSR) database. Patients with mild stroke (defined as National Institutes of Health Stroke Scale ≤5) receiving the rt-PA therapy and without rt-PA therapy were matched in 1:2 for age, sex, stroke severity and etiologic subtype. A total of 134 rt-PA-treated patients were matched to 249 non-rt-PA-treated patients in the study. Among them, 104 (76%) rt-PA-treated patients with mild stroke had good outcome after 3 months compared with 173 (69.5%) non-rt-PA-treated matching cases (odds ratio [OR], 1.48; 95% confidence interval [CI], 0.91-2.43; P = 0.12). Compared with non-rt-PA-treated group, rt-PA-treated patients had good outcome after 3 months in those with stroke subtype of large-artery atherosclerosis (LAA) (80.5% vs 65.1%; OR, 2.19; 95%CI, 1.14-4.21; P = 0.02). For patients with mild stroke, intravenous rt-PA treatment may be effective. Patients with stroke subtype of LAA might benefit more from rt-PA treatment.