CD20-specific antibodies are a common therapy for B cell malignancies and autoimmune disorders, but the mechanism of the resulting B cell depletion has been unclear. This study shows that the liver has a central role. Using intravital two-photon imaging in mice and a fluorescence-tagged reporter to mark Kupffer cells, the authors showed that B cells circulating in the liver sinusoids arrested on Kupffer cells and were engulfed by these cells after injection with a CD20-specific monoclonal antibody. This process was impaired in mice lacking FcRγ, which shows that engagement of Fc receptors on Kupffer cells is required for antibody-dependent cellular phagocytosis of B cells. Kupffer cells were also shown to engulf spontaneously developing lymphoma cells in mice receiving CD20-specific antibody therapy. The authors predict that depletion of malignant lymphoid cells in humans will be more efficient for recirculating tumour cells than those in secondary lymphoid organs.