Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system. Familial MS is arbitrarily defined as a type of MS that runs in families with one or more first- to third-degree relatives in addition to the index case affected by MS. The aim of this article is to report a unique case of familial MS from Saudi Arabia with two novel variants in the HLA-DRB1 gene that may contribute to the pathogenesis. We observed an unfavorable response to interferon therapy and successful treatment using fingolimod therapy. This observation needs further study, including whether this lack of response is really specific to interferon treatment or possibly a chance occurrence. This family work-up illustrates the importance of genetic testing in identifying variants associated with familial MS, especially if more than two members of the same family are affected. Although this genetic tool is used mainly for research purposes, it had clinical implications for our patient, including the appropriate selection of disease-modifying therapy and prognostic counseling. Further large-scale studies are needed to expand the genetic spectrum of familial MS with clinical and pharmacologic correlation.