Background: Until recently, few therapeutic options, other than symptomatic treatment, were available for patients with primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only approved treatment in this indication, and only since 2017. However, many patients in France are receiving off-label treatments for PPMS, mainly rituximab, mycophenolate mofetil, methotrexate, cyclophosphamide, and azathioprine. Objective: To evaluate published data concerning the efficacy of these five treatments frequently used as off-label disease-modifying therapies. Methods: We reviewed and summarized the studies published in Pubmed since the inception of the database. Results: Evidence from randomized controlled trials is lacking to support the use of these treatments as disease-modifying therapies in PPMS. Conclusion: The literature lacks dedicated studies to support the off-label use of these disease-modifying therapies in PPMS. However, some limited data are available in the literature suggesting that the use of rituximab and cyclophosphamide could potentially be of some interest in specific subpopulations.