Background <p> Multiple sclerosis is a chronic neurological disorder affecting the central nervous system. It is classified as the foremost neurological contributor to disability among young adults. In 2017, Ocrelizumab, a humanized IgG1 monoclonal anti-CD20 antibody, received approval for the treatment of relapsing and progressive forms of MS.</p> Results <p>This prospective cohort investigation sought to track total CD19 B-cell counts throughout the course of B-cell depletion therapy in MS patients, correlating these counts with disease activity. A total of 30 Egyptian patients diagnosed with Relapsing-Remitting Multiple Sclerosis, according to the 2017 McDonald criteria, were enrolled in the study. All participants underwent comprehensive assessments at baseline, 6 months, and 12 months post-therapy. Clinical, radiological, and laboratory assessment involved cerebral and spinal MRI, and CD19 B-cell counts were determined through flow cytometry for immunophenotyping. Our patients were predominantly female (73.3%). We observed a significant drop in CD19 B-cell counts from a median of 30.65 cells/µL pre-treatment to 2.76, 4.43, and 4.74 cells/µL at 1, 6, and 12 months, respectively. This B-cell depletion was strongly linked to a substantial reduction in the median Annualized Relapse Rate, which decreased from 2.0 before treatment to 0 after 12 months of Ocrelizumab therapy. Clinical outcomes showed a drop in the EDSS median score from 4.5 pre-treatment to 3.5 at 6 months and 2.5 at 12 months. Radiologically, most patients maintained a stable lesion burden in their brain and spinal cord in both number and size. A statistically significant reduction (<i>p</i> &lt; 0.05) in gadolinium-enhancing lesions was noted after 12 months.</p> Conclusion <p> Ocrelizumab proved highly effective in reducing relapses, preventing disability progression, and decreasing disease activity (both clinical and radiological) in our group of Egyptian MS patients over 12 months using a fixed dose schedule.</p>