AbstractBackground and PurposeIschemic diffusion‐weighted imaging‐fluid‐attenuated inversion recovery (DWI‐FLAIR) mismatch may be useful in guiding acute stroke treatment decisions given its relationship to onset time and parenchymal viability; however, it relies on subjective grading. Radiomics is an emerging image quantification methodology that may objectively represent continuous image characteristics. We propose a novel radiomics approach to characterize DWI‐FLAIR mismatch.MethodsIschemic lesions were visually graded for FLAIR positivity (absent, subtle, obvious) among consecutive large vessel occlusion stroke patients who underwent hyperacute MRI. Radiomic features were extracted from within the lesions on DWI and FLAIR. The DWI‐FLAIR mismatch radiomics signature was built with features systematically selected by a cross‐validated ElasticNet linear regression model of mismatch.ResultsWe identified 103 patients with mean age 68 ± 16 years; 63% were female. FLAIR hyperintensity was absent in 25%, subtle in 55%, and obvious in 20%. Inter‐rater agreement for visual grading was moderate (Κ = .58). The radiomics signature of DWI‐FLAIR mismatch included native FLAIR histogram kurtosis and local binary pattern‐filtered FLAIR gray‐level cluster shade; both correlated with visual grading (ρ = –.42, p < .001 and ρ = .40, p < .001, respectively).ConclusionsRadiomics can describe DWI‐FLAIR mismatch and may provide objective, continuous biomarkers for infarct evolution using clinical‐grade images. These novel biomarkers may prove useful for treatment decisions and future research.