Aim: Monoclonal anti-CD20 antibody ocrelizumab primarily depletes B cells and is approved to treat multiple sclerosis (MS). Although it is known that ocrelizumab does not completely deplete B cells and B cell reconstitution can be detected in some MS patients, little is known about phenotypes of these remaining as well as repopulating B cells and whether they associate to disease outcomes and/or to changes in other immune cell types. Method: In this study, we performed comprehensive in-depth immune profiling of ocrelizumab-treated MS patients after short-term (a cohort of 31 patients) or long-term (a cohort of 50 patients) treatment using mass cytometry and two antibody panels (targeting 63 protein markers). Results: Depletion of CD20+ B and T cells could be detected as early as 2 weeks after treatment, whereas 6 months after treatment the repopulation of these cells could be quantified in some patients. Majority of repopulating B cells were CD20+CD27- B cells with increased transitional phenotypes, while CD27+ memory B cells were rarely repopulated. Patients with B cell repopulation showed less abundance of CD45RO+ICOS+ T cell subsets, compared to the ones without B cell repopulation, suggesting reduced activation of the immune responses. In addition, we characterized differential phenotypic profiles of NK and myeloid cells including granulocytes in these patients. Conclusion: Our results provide comprehensive immune profiles after ocrelizumab treatment, which may help to better understand its complex effects on patients’ immune system.