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Background and purpose: Lesion remyelination preserves axonal integrity in animal models of multiple sclerosis (MS), but an in vivo demonstration of its protective effect on surrounding tissues in humans is lacking. Methods: Nineteen persons with MS were enrolled in a cohort study and underwent two positron emission tomography (PET)/magnetic resonance imaging (MRI) scans 1–4 months apart. Voxelwise maps of Pittsburgh compound B distribution volume ratio, reflecting myelin content, were used to calculate an index of baseline demyelination, and of dynamic demyelination and remyelination over the follow‐up in 549 single white matter lesions. Changes in fractional anisotropy and mean diffusivity, reflecting microstructural damage, were calculated in the proximal and distal 3‐mm‐thick rings surrounding each lesion, and used to classify perilesional microstructure as "preserved" or "worsening" over the follow‐up. Mixed‐effect linear models and logistic regressions were employed to investigate whether PET‐derived lesional indices were associated with changes in MRI metrics in perilesions, and to identify which of them best predicted the microstructural evolution of perilesions over time. Results: A higher index of remyelination, and a lower index of baseline and dynamic demyelination in lesions were associated with a less severe microstructural deterioration of the corresponding proximal and distal perilesions over time (p‐value range: <0.001–0.012), but the index of remyelination was the best predicting variable of perilesional fate. For every extra 1% of remyelination within each lesion, the probability of the corresponding perilesional microstructure remaining preserved over time increased by 39% (odds ratio = 6.62, 95% confidence interval = 2.16–20.32, p < 0.001). Conclusions: Intralesional remyelination is associated with the microstructural preservation of surrounding tissues, possibly preventing neuroaxonal damage resulting from Wallerian degeneration. [ABSTRACT FROM AUTHOR]