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Background: Clinical-diffusion mismatch (CDM) and perfusion-diffusion mismatch (PDM) are used to select patients for endovascular thrombectomy (EVT) in the late-window period. As CDM well reflects true penumbra, we hypothesized that patients with CDM and PDM would respond better to EVT than those with PDM only at the late-window period. Methods: Acute ischemic stroke patients who received EVT 6–24 h after stroke onset were included. PDM (perfusion-/diffusion-weighted image (DWI) lesion volume >1.8) was used to select candidates for EVT in this time-period in our center. CDM was defined according to the DAWN trial criteria. Response to EVT was compared between patients with and without CDM. Early neurological improvement (ENI) was defined as improvement >4 points on National Institutes of Health Stroke Scale (NIHSS) score 1 day after EVT. Multivariable analysis was performed to investigate independent factors associated with ENI. The correlation between DWI lesion volume and NIHSS score was investigated in those with and without CDM. Results: Among 94 patients enrolled, all patients had PDM and 44 (46.3%) had CDM. Forty-eight patients (51.1%) showed ENI. The prevalence of hypertension, initial NIHSS score, improvement in NIHSS score after EVT, and prevalence of ENI were greater in patients with CDM than those without. ENI was independently associated with onset-to-door time (odds ratio [95% confidence interval]: 0.998 [0.997–1.000]; p = 0.042), complete recanalization (23.912 [2.238–255.489]; p = 0.009), initial NIHSS score (1.180 [1.012–1.377]; p = 0.034), and the presence of CDM (5.160 [1.448–18.386]; p = 0.011). The correlation between DWI lesion volume and initial NIHSS score was strong in patients without CDM (r = 0.731) but only moderate in patients with CDM (r = 0.355). Conclusion: Patients with both CDM and PDM had a better response to late-window EVT than those with PDM only. [ABSTRACT FROM AUTHOR]