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Background: The homeostatic chemokines CCL19 and CCL21 are involved in carotid plaque vulnerability and post-ischemic neuroinflammatory responses. This study aimed to examine the prognostic values of CCL19 and CCL21 in ischemic stroke., Methods: Plasma CCL19 and CCL21 were measured in 4483 ischemic stroke patients from two independent cohorts of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) and IIPAIS (Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke), and participants were followed up at 3 months after stroke. The primary outcome was the composite outcome of death or major disability. The associations of CCL19 and CCL21 levels with the primary outcome were examined., Results: In CATIS, multivariable-adjusted odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 compared with the lowest quartiles were 2.06 and 2.62, respectively. In IIPAIS, odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 were 2.81 and 2.78 compared with the lowest quartiles, respectively. In the pooled analysis of the two cohorts, odds ratios of the primary outcome associated with the highest quartiles of CCL19 and CCL21 were 2.24 and 2.66, respectively. Similar findings were observed in the analysis with major disability, death, and the composite outcome of death or cardiovascular events as the secondary study outcomes. Adding CCL19 and CCL21 to conventional risk factors significantly improved risk reclassification and discrimination for adverse outcomes., Conclusions: Both CCL19 and CCL21 levels were independently associated with adverse outcomes within 3 months after ischemic stroke and should be further investigated for risk stratification and potential therapeutic targets of ischemic stroke., (© 2023 European Academy of Neurology.)