The continued efficacy of B-cell depletion in rheumatoid arthritis (RA) depends on repeated cycles of anti-CD20 treatment to maintain low levels of B cells. It is surprising that this significant manipulation of the humoral immune system is remarkably safe with repeated treatment and that rates of adverse effects remain stable, and may even decline, over subsequent courses. Although responses to vaccines and probably to new antigens are diminished, adaptive immunity nevertheless functions adequately despite markedly restricted B-cell numbers. In the 10 years or so since the widespread use of B-cell depletion, there is little to suggest that a long-term paucity of B cells puts patients at risk for malignancy or opportunistic infections, nor that it leads to treatment-resistant RA or complications. While time will tell whether this major alteration of the immune system has other consequences, it is remarkable that drastic reduction of B-cell numbers over the long term is tolerated so well, and that it maintains efficacy in RA therapy.