Molecular mechanisms responsible for acute relapse of multiple sclerosis (MS) remain currently unknown. The aim of this study is to identify the relapse-specific biomarker genes in T lymphocytes of relapsing-remitting MS (RRMS). Total RNA of CD3+ T cells isolated from six RRMS patients taken at the peak of acute relapse and at the point of complete remission was processed for DNA microarray analysis. We identified a set of 43 differentially expressed genes (DEG) between acute relapse and complete remission. By using 43 DEG as a discriminator, hierarchical clustering separated the cluster of relapse from that of remission. The molecular network of 43 DEG investigated by KeyMolnet, a bioinformatics tool for analyzing molecular interaction on the curated knowledge database, showed the most significant relationship with aberrant regulation of gene expression by the nuclear factor-kappa B (NF-kappaB) in T cells during MS relapse. These results support the logical hypothesis that NF-kappaB plays a central role in triggering molecular events in T cells responsible for induction of acute relapse of MS, and suggest that aberrant gene regulation by NF-kappaB on T-cell transcriptome might serve as a molecular biomarker for monitoring the clinical disease activity of MS.