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Twenty-four patients with the first episode of acute unilateral ON were compared with 56\u00a0healthy volunteers with normal vision. Additionally, longitudinal analysis 3 and 6\u00a0months after ON was performed in 17 patients. Multivariate analysis of variance across baseline DWI metrics revealed a greater secondary partial volume fraction (f2) in patients. In the longitudinal analysis, a multivariate effect of time was observed only when adjusted for the affected side and time since onset; however, univariate post hoc tests were nonsignificant. An unadjusted model stratified according to clinical outcomes (best-corrected visual acuity [BCVA] and contrast sensitivity) indicated lower overall fractional anisotropy (FA) in patients with incomplete recovery. In the correlation analysis, baseline FA and oximetry (venous saturation and arteriovenous difference) predicted follow-up BCVA, whereas axial diffusivity predicted follow-up oximetry. 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