Abstract Background The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. Methods Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = ‘Walk unaided’, 2 = ‘With walking aid’ and 3 = ‘Bed-bound’. The margin used to establish non-inferiority was a detrimental change of −0.4 in the mean difference between arms. Results One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30–87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was −0.12 to 0.6. Since −0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2–3 AE compared with six (11%) patients in the SF arm (p = 0.093). Conclusion For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. Clinical Trial Registration Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.