B cell depletion by the anti-CD20 antibody ocrelizumab is effective in relapsing-remitting (RR) and primary progressive (PP) multiple sclerosis (MS). We investigated immunological changes in peripheral blood of a real- world MS cohort after 6 and 12 months of ocrelizumab. All RRMS and most PPMS patients (15/20) showed treatment response. Ocrelizumab not only reduced CD20+ B cells, but also numbers of CD20+T cells. Absolute numbers of monocytes, dendritic cells and CD8+T cells were increased, while CD56hi natural killer cells were reduced after ocrelizumab. The residual B cell population shifted towards transitional and activated, IgA+ switched memory B cells, double negative B cells, and antibody- secreting cells. Delaying the treatment interval by 2–3 months increased mean B cell frequencies and enhanced naive B cell repopulation. Ocrelizumab reduced plasma levels of interleukin(IL)-12p70 and interferon (IFN)-α2. These findings will contribute to understanding ineffective treatment responses, dealing with life-threatening infections and further unravelling MS pathogenesis.