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The aim of the study is the identification of genetic factors that influence the long-term response to interferon-β (IFNβ) (4-year follow-up). We performed a genome-wide association study in 337 IFNβ-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNβ-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10−4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2and TBXAS1,that were significantly downregulated after IFNβ stimulation in HC (P=3.1 × 10−9and 5.6 × 10−10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1appeared downregulated upon IFNβ administration (β=−0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3and GRIK2), confirming its potential role in the response to IFNβ.