Background: Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for the treatment of relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS). During the phase III trials, 1.5% of patients developed low immunoglobulin G (IgG) values after 2-3 years of OCR treatment. JCV antibody index was not studied during the phase III trials. The impact of long-term B-cell suppression on IgG levels and JCV index is unknown. Objectives: As part of the ACAPELLA trial, a prospective study with a primary objective of assessing OCR-associated adverse events (AEs) in a real-world MS population, we sought to evaluate the impact of OCR treatment on immunoglobulin levels and JCV index. Methods: The study includes all subjects receiving OCR at the Elliot Lewis Center followed prospectively since March 2017. Subjects are monitored for occurrence of infections and other serious adverse events (SAEs) and have biannual assessments of serum immunoglobulin levels and JCV antibody index. Results: As of January 2021, 315 subjects with baseline IgG levels were enrolled. 218 subjects had reached 12 months of treatment, 156 subjects had reached 18 months, 139 subjects had reached 24 months, and 82 subjects had reached 30 months. Ten patients (3%) with baseline normal IgG had at least one laboratory value with low IgG. Only 5 patients (1.5%) developed persistent hypogammaglobulinemia. Thirteen subjects (4%) had IgG levels below the lower limit of normal (LLN) at baseline. Nine of 13 patients had subsequent data to analyze. All 9 subjects had IgG levels that remained below or near the LLN. Three-hundred and ten subjects had a baseline JCV index. One-hundred and three (33%) had an index 1.5. In our year-four data, 14 patients (5%) showed a drop in JCV index ? 0.5. These JCV index changes were not associated with a corresponding decline in IgG levels. Conclusions: In this cohort of patients, persistent hypogammaglobulinemia was infrequent and was not associated with an increased risk of infection. Five percent of patients treated with OCR for 6-24 months had a drop in JCV index of ? 0.5 with no corresponding change in IgG. Caution should be exercised when interpreting JCV index in patients previously treated with OCR.