Resistance to therapeutic antibodies in chronic lymphocytic leukaemia (CLL) is common. In this study, we show that therapeutic antibodies against CD62L (CD62L-Ab) or CD20 (obinutuzumab) were able to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADP) in primary cultures of CLL cells. CLL cells derived from patients with active disease requiring treatment displayed resistance to these antibodies, whereas patients with stable disease were sensitive. Using enrichment strategies and transcriptomic analyses, we show that antibody-dependent tumour cell killing was FcγR-dependent and mediated by macrophages. Moreover, we show that resistance cannot be attributed to total numbers or established subtypes of monocytes/macrophages, or the efficiency with which they bind an immune complex. Rather, ADCC/ADP resistance was due to reduced signalling activity through the activating FcγRs resulting in the transfer of dominance to the inhibitory FcγRIIb within macrophages. Most significantly, we show that resistance is an actionable event that could be reversed using inhibitors of FcγRIIb signalling in primary cultures of CLL cells that were previously insensitive to obinutuzumab or CD62L-Ab.