Abstract Background Enhancing remyelination in MS might improve function and protect axons from future damage. Lesion magnetisation transfer ratio (MTR) is sensitive to myelin content, and may be a useful measure for trials evaluating potential remyelinating agents. Objective Estimating sample sizes required for a parallel group, placebo-controlled trial in MS using change in mean MTR of all T2 lesions as a primary outcome measure. Methods The primary sample size calculation was derived from data from a natural history study of relapsing remitting MS ( n =18). The MTR values observed in demyelinated and remyelinated lesions in an ex vivo study were used to estimate the effect of remyelination on lesion MTR. The ex vivo data were also used to independently calculate sample sizes in order to inform the robustness of the in vivo estimates. Results Calculations suggest that 30% remyelination of T2 lesions could be detected with 80% power in 38 (95% confidence interval 12–96) patients per arm based on the in vivo data, and in 66 per arm based on the ex vivo data. Conclusion The sample sizes derived are in a range that makes MTR a feasible outcome measure for proof-of-concept trials of putative therapies achieving remyelination in MS lesions.