OBJECTIVE: To assess the pathological mechanisms contributing to white matter (WM) lesion expansion or contraction and remyelination in multiple sclerosis (MS). METHODS: We assessed 1,613 lesions in 49 people with relapsing-remitting MS in the CCMR-One bexarotene trial (EudraCT 2014-003145-99). We measured lesion orientation relative to WM tracts, surface-in gradients and veins. Jacobian deformation was used to assess lesion expansion over 6 months, while magnetization transfer ratio (MTR) imaging was used to assess remyelination. RESULTS: At baseline, 33% of lesions were aligned with veins, 2% along WM tracts, 0% with surface-in gradients, and 4% orthogonal to veins. No significant differences were observed in lesion shape, while lesions aligned with surface-in gradients and with veins had lower volume compared to all remaining orientations. At follow-up, 13% of lesions expanded and 7% contracted. The directions for both expansion and contraction were 18% and 8%, respectively, along WM tracts, 20% and 15% parallel to veins, 22% and 23% orthogonal to veins and 0% and 1% along surface-in gradients. Bexarotene had no effect on lesion expansion or contraction, but MTR significantly increased in lesions aligned with surface-in gradients and veins. INTERPRETATION: Lesion expansion and shrinkage are affected by venous and WM tract factors, but these do not influence bexarotene's capacity to promote remyelination. This, instead, appears to be affected by surface-in factors. To limit lesion expansion and maximize tissue repair, multiple processes may need to be targeted.