Background: Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for treatment of relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS). In the OPERA trials, circulating CD19+ B-cell counts dropped to zero within 14 days of OCR infusion. Median time to repletion, defined as >79 cells/uL, was 72 weeks (range 27-175 weeks). In the OPERA trial, up to 5% of patients showed B-cell repletion. The timing of B-cell repletion and the relationship between disease breakthrough and MS is unclear. Objectives: As part of the ACAPELLA trial (a prospective study assessing OCR-associated adverse events in a real-world population) we sought to describe the incidence and degree of B-cell repletion in our patients treated with ocrelizumab and to evaluate any correlation between CD19+ cell count, demographics, AEs, and breakthrough disease. Methods: All subjects who had at least 2 cycles of OCR at the Elliot Lewis Center since March 2017 had serum immunoglobulin levels, JCV antibody titers, and lymphocyte subsets on the day of each infusion prior to receiving OCR. Subjects were followed prospectively and monitored for the occurrence of infections and other serious adverse events (SAEs). We defined 4 groups: non-repleters with 0 – 9 cells/µL, mild repleters with 10 – 49 cells/µL, moderate repleters with 50 – 79 cells/µL, and marked repleters with ?80 cells/µL. Subjects were assigned to these subgroups based on their highest CD19 value at any cycle. Results: As of January 2021, 272 patients had CD19 values drawn. One hundred ninety-seven subjects (72%) were non-repleters, 53 subjects (19%) were mild repleters, 10 subjects (4%) were moderate repleters, and 12 subjects (4%) were marked repleters. There was no relationship between CD19 repletion and clinical and/or MRI relapse. Conclusions: Although many patients displayed some B-cell repletion prior to their next dose (75 subjects, 28%), CD19 counts of >79 cells/ µL were uncommon (12 subjects, 4%). Mild B-cell repletion was fairly common after two cycles of OCR, but with repeated dosing, a greater proportion of patients were non-repleters, suggesting that cumulative exposure to OCR results in greater depletion. Moderate or marked repleters (>50 cells/ µL) had a tendency to remain repleters with subsequent infusions. Thus far, we have found no significant correlation between B-cell repletion and either disease activity or adverse events.