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Objective Takayasu arteritis (TAK)-related stroke and large-artery atherosclerosis (LAA)-related stroke share overlapping clinical features but differ fundamentally in pathophysiology and treatment strategies. Differentiating these two aetiologies remains a diagnostic challenge with critical therapeutic implications. We aimed to compare the clinical profiles, imaging characteristics and outcomes of TAK- versus LAA-related stroke to provide insights for diagnosis and management.Patients and methods We conducted a multicentre comparative study using nationwide prospective registry cohorts in China. Among 926 patients with TAK, 80 patients with stroke were included. In addition, 372 patients with LAA-related stroke were selected from the China National Stroke Registry-III cohort (n=14 146). Clinical and imaging characteristics, traditional stroke risk factors and outcomes were analysed and compared. Subgroup analyses were performed according to the presence of atherosclerosis in TAK. Propensity score weighting was performed as a sensitivity analysis.Results Compared with LAA-related stroke, TAK-related stroke was younger, with a strong female predominance and lower prevalence of vascular risk factors and appeared to have a higher proportion of favourable functional outcomes (modified Rankin Scale 0–2: 93.2% vs 72.6%, p=0.0002), although direct comparison was limited by differences in follow-up structure and assessment timing. Furthermore, patients with TAK tended to show distinct imaging features, including predominant extracranial artery involvement and anterior circulation infarctions located in the subcortical/deep white matter. Among patients with TAK-related stroke, those with coexisting atherosclerosis were older, had longer disease duration and had a greater risk of supra-aortic complications and a higher rate of endovascular interventions.Conclusions This study highlights distinct clinical and imaging profiles between TAK- and LAA-related strokes. It also provides a comparative analysis of TAK-related stroke with and without atherosclerosis, revealing differences in risk factors, vascular characteristics and intervention needs. These findings provide a descriptive framework that may assist aetiological differentiation and hypothesis generation for future studies.