Background: Anti-CD20 monoclonal antibodies are highly effective for RMS treatment. Ocrelizumab (OCR) is standard, while Rituximab (RTX) is an alternative. The impact of anti-CD20 therapies on immune markers remains understudied, though deficiencies are frequently observed and have been associated with increased risk of infection. Our objective is to characterize and compare lymphocyte, neutrophil, and immunoglobulin levels in OCR- versus RTX-treated persons with RMS. Methods: This retrospective chart review included RMS patients on OCR or RTX (2017–2023). Pre- and post-treatment levels of lymphocytes, neutrophils, and immunoglobulins (IgG, IgA, IgM) were analyzed. Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models were used for survival analysis. Results: 350 patients (OCR=175, RTX=175) were included. The mean treatment length was 60.9 (SD 19.1) months for OCR and 42.7 (SD 19.5) months for RTX. RTX was associated with a significantly shorter time to IgM deficiency (29.6 vs. 40.0 months, p=0.02). Cox analysis confirmed RTX increased IgM deficiency risk (HR=1.54, 95% CI: 1.06-2.23, p=0.02). No differences were seen for lymphocytes, neutrophils, IgG, or IgA. Conclusions: RTX was associated with a shorter time to and increased risk of IgM hypogammaglobulinemia compared to OCR, highlighting the importance of long-term monitoring. Further research is needed to guide treatment decisions.