Anti-CD20 monoclonal antibodies (mAbs) are used to treat multiple sclerosis (MS), including rituximab, ocrelizumab, ofatumumab, and ublituximab. These therapies target the CD20 receptor on B cells, leading to B-cell depletion and improved clinical outcomes. Ocrelizumab is the only CD20 mAb approved for primary progressive MS. These therapies are effective in reducing MRI lesion activity and clinical relapses but have safety concerns, including infusion-related reactions, hypogammaglobulinemia, and decreased vaccine response. Alternative dosing schedules may help mitigate these risks. Biosimilars could increase availability. Despite their efficacy, CNS-penetrant therapies are still needed to address compartmentalized inflammation in MS. B cells play a significant role in MS pathogenesis, interacting with T cells and contributing to inflammation. Anti-CD20 mAbs target B-cell maturation and function, leading to B-cell depletion. These therapies have distinct molecular structures, target epitopes, and pharmacological features. Ocrelizumab has greater ADCC than CDC, while rituximab has greater CDC than ADCC. Clinical trials show these therapies are effective in reducing relapses and disability progression in MS. However, relative efficacy between therapies is not well established. Immunogenicity is a concern, with anti-drug antibodies (ADAs) detected in some patients. Hypogammaglobulinemia is a potential long-term complication, increasing infection risk. Ocrelizumab has lower risk of hypogammaglobulinemia compared to rituximab. Adverse events include infusion-related reactions, infections, and malignancies. Ocrelizumab has a lower incidence of serious infections compared to rituximab. Vaccine response is impaired with B-cell depletion, but T-cell responses may be preserved. Pregnancy and breastfeeding are not recommended during anti-CD20 mAb therapy. Pre-treatment testing includes CBC, CMP, and hepatitis B serologies. Safety monitoring includes regular CBC, CMP, and Ig levels. Extended interval dosing may improve vaccine response and reduce hypogammaglobulinemia risk. Future research focuses on optimizing dosing schedules and developing CNS-penetrant therapies to better address MS pathology.Anti-CD20 monoclonal antibodies (mAbs) are used to treat multiple sclerosis (MS), including rituximab, ocrelizumab, ofatumumab, and ublituximab. These therapies target the CD20 receptor on B cells, leading to B-cell depletion and improved clinical outcomes. Ocrelizumab is the only CD20 mAb approved for primary progressive MS. These therapies are effective in reducing MRI lesion activity and clinical relapses but have safety concerns, including infusion-related reactions, hypogammaglobulinemia, and decreased vaccine response. Alternative dosing schedules may help mitigate these risks. Biosimilars could increase availability. Despite their efficacy, CNS-penetrant therapies are still needed to address compartmentalized inflammation in MS. B cells play a significant role in MS pathogenesis, interacting with T cells and contributing to inflammation. Anti-CD20 mAbs target B-cell maturation and function, leading to B-cell depletion. These therapies have distinct molecular structures, target epitopes, and pharmacological features. Ocrelizumab has greater ADCC than CDC, while rituximab has greater CDC than ADCC. Clinical trials show these therapies are effective in reducing relapses and disability progression in MS. However, relative efficacy between therapies is not well established. Immunogenicity is a concern, with anti-drug antibodies (ADAs) detected in some patients. Hypogammaglobulinemia is a potential long-term complication, increasing infection risk. Ocrelizumab has lower risk of hypogammaglobulinemia compared to rituximab. Adverse events include infusion-related reactions, infections, and malignancies. Ocrelizumab has a lower incidence of serious infections compared to rituximab. Vaccine response is impaired with B-cell depletion, but T-cell responses may be preserved. Pregnancy and breastfeeding are not recommended during anti-CD20 mAb therapy. Pre-treatment testing includes CBC, CMP, and hepatitis B serologies. Safety monitoring includes regular CBC, CMP, and Ig levels. Extended interval dosing may improve vaccine response and reduce hypogammaglobulinemia risk. Future research focuses on optimizing dosing schedules and developing CNS-penetrant therapies to better address MS pathology.