Rituximab and Ocrelizumab in Multiple Sclerosis: Does Comparative Evidence Redefine Anti-CD20 Therapy?

B-cell depletion has transformed multiple sclerosis treatment, with rituximab and ocrelizumab providing highly effective CD20-directed therapy. This narrative review aims to critically compare these agents from the mechanistic, clinical, safety, regulatory, and economic perspectives. Despite their shared target, differences in pharmacology, dosing, regulatory status, and cost may influence treatment selection. Observational studies generally suggest similar effectiveness, although interpretation is limited by confounding and heterogeneous treatment strategies. The randomized, double-blind OVERLORD-MS trial provides the strongest direct evidence, demonstrating non-inferiority of rituximab to ocrelizumab for suppression of new or enlarging inflammatory lesions on magnetic resonance imaging (MRI) in newly diagnosed relapsing MS. However, evidence remains insufficient to establish equivalence for disability progression, long-term outcomes, or rare and cumulative adverse events. Uncertainty persists regarding infections, hypogammaglobulinemia (reduced immunoglobulin levels), pregnancy, optimal dosing, and long-term immune effects. Rituximab’s substantially lower cost could improve access to high-efficacy treatment; however, current evidence does not directly support assuming universal interchangeability with ocrelizumab.