A hypothesis is formulated on viral interaction between HHV-6A and EBV as a pathogenic mechanism in Multiple Sclerosis (MS). Evidence of molecular and genetic mechanisms suggests a link between HHV-6A infection and EBV activation in the brain of MS patients leading to intrathecal B-cell transformation. Consequent T-cell immune response against the EBV-infected cells is postulated as a pathogenic basis for inflammatory lesion formation in the brain of susceptible individuals. A further link between HHV-6A and EBV involves their induction of expression of the human endogenous retrovirus HERV-K18-encoded superantigen. Such virally induced T-cell responses might secondarily also lead to local autoimmune phenomena. Finally, research recommendations are formulated for substantiating the hypothesis on several levels: epidemiologically, genetically, and viral expression in the brain.