OBJECTIVES: Brain atrophy is associated with cognitive deficits in patients with clinically isolated syndrome (CIS) and can predict conversion to clinical definite multiple sclerosis. The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMDs) on brain atrophy in patients with CIS.METHODS: Eligible placebo-control randomized clinical trials of patients with CIS that had reported changes in brain volume during the study period were identified by searching the MEDLINE, SCOPUS, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. This meta-analysis adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses.RESULTS: Three eligible studies were identified, comprising 1362 patients. The mean percentage change in brain volume was found to be significantly lower in DMD-treated patients versus placebo-treated subgroups (standardized mean difference [SMD]: = -0.13, 95% confidence interval [CI]: -0.25, 0.01; p = 0.04). In the subgroup analysis of the two studies that provided data on brain-volume changes for the first (0-12 months) and second (13-24 months) year of treatment, DMD attenuated brain-volume loss in comparison with placebo during the second year (SMD = -0.25; 95% CI: -0.43, -0.07; p < 0.001), but not during the first year of treatment (SMD = -0.01; 95% CI: -0.27, 0.24; p = 0.93). No evidence of heterogeneity was found between estimates, while funnel-plot inspection revealed no evidence of publication bias.CONCLUSIONS: DMDs appear to attenuate brain atrophy over time in patients with CIS. The effect of DMDs on brain-volume loss is evident after the first year of treatment.