The Epstein–Barr virus (EBV) is recognized as the primary infectious agent linked to multiple sclerosis (MS), although the presence of EBV infection alone does not suffice to explain the progression of the illness, given that most patients infected with EBV do not manifest MS. This review examines host genetic profiles that may increase MS susceptibility among EBV-exposed individuals, with emphasis on HLA-mediated antigen presentation, EBV-specific immune responses, and non-HLA immune pathways. The strongest genetic risk signal is HLA-DRB115:01, often within the HLA-DR15 haplotype, which may promote presentation of EBV-derived antigens such as EBNA1 and facilitate CD4+ T-cell activation, molecular mimicry, and CNS-directed autoimmunity. In contrast, HLA-A02:01 appears protective, potentially through more effective CD8+ T-cell-mediated control of EBV-infected B cells; therefore, absence of HLA-A02:01 may represent an important risk-modifying feature. Emerging evidence also implicates HLA-E01:01, particularly in individuals with a history of infectious mononucleosis, suggesting a role for altered NK-cell and CD8+ T-cell regulation in EBV-associated MS risk. Beyond HLA, non-HLA loci such as CD86, CD40, IL2RA, and IL7R may amplify EBV-driven immune activation by modulating antigen-presenting cell function, B/T-cell costimulation, cytokine signaling, and immune tolerance. High anti-EBNA1 antibody titers, especially in HLA-DRB115:01-positive individuals, may serve as an immunological marker of dysregulated host–EBV interaction. Overall, the most plausible high-risk profile combines EBV positivity, infectious mononucleosis or elevated anti-EBNA1 responses, HLA-DRB115:01 positivity, absence of HLA-A02:01, possible HLA-E01:01 carriage, and increased non-HLA immune risk burden. These profiles remain research-based risk-enrichment models rather than clinical prediction tools. Longitudinal investigations focusing on functional genomics, single-cell methodologies, HLA peptidomics, and EBV vaccination are required to understand the reasons behind the selective development of MS in certain EBV-infected individuals and to shape preventive strategies.