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This study examined the associations between gait variability based on common spatiotemporal parameters and energetic cost of walking in persons with multiple sclerosis.Eighty-six persons with multiple sclerosis underwent the 6-min walk while wearing a portable metabolic unit. The cost of walking was generated by dividing the net steady-state VO2 (milliliter per kilogram per minute) by walking speed during the 6-min walk. Participants further completed two trials of walking on the GAITRite mat at a self-selected pace for measuring spatiotemporal parameters. Variability of step length, step time, stride length, swing time, stance time, stride velocity, and single- and double-support time was indexed by the coefficient of variation.Variability in the spatiotemporal variables and Expanded Disability Status Scale scores were significantly correlated with cost of walking (i.e., ρ = 0.25–0.36). Multivariate analysis revealed that disability (Expanded Disability Status Scale: β = 0.186), stance time variability (β = 1.446), and step length variability (β = −1.216) explained significant variance (R2 = 0.38, P < 0.001) in cost of walking.We provide evidence of the positive association between gait variability and cost of walking during overground walking in persons with multiple sclerosis. The findings highlight the need for interventions aiming to reduce gait variability, thereby reducing the energetic demands of walking in this population.