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Introduction: One class of potential post-stroke restorative therapy focuses on promoting axon outgrowth by blocking myelin-based inhibitory proteins such as myelin-associated glycoprotein (MAG). The aim of the current study was to extend preclinical and clinical findings of GSK249320, an IgG1-type monoclonal antibody to MAG, to explore effects on motor outcomes after stroke.Methods: This was a phase IIb double-blind, randomized, placebo controlled study (GSK funded; clinicaltrials.gov # NCT01808261). At 30 international sites, patients with ischemic stroke 24-72 hours prior and deficits in gait were randomized to two IV infusions of GSK249320 or placebo. Primary outcome measure was change in gait velocity from baseline to Day 90.Results: A total of 134 subjects were randomized. The two groups were overall well matched at baseline. The study was stopped at the pre-specified interim analysis because the treatment difference met the predefined futility criteria cutoff. Secondary endpoints, including gait analyzed categorically and upper extremity function (Box & Blocks score), were concordant. The two IV infusions of GSK249320 were well tolerated. Although direct evidence that the therapy reached the biological target was not available, indirect evidence of target binding was suggested by the substantial reduction in free MAG plasma levels with GSK249320 treatment.Conclusions: The monoclonal antibody GSK249320 administered IV within 72 hours of stroke onset demonstrated no improvement in gait velocity as compared to placebo. The antibody was well tolerated and showed low immunogenicity, findings that may prove useful to future studies aiming to use a monoclonal antibody to modify activity in specific biological pathways in order to improve recovery from stroke.