Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1–3]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4,5]. FcγRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcγRII-deficient mice are prone to immune-mediated disease [7–9]. The gene encoding FcγRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB × New Zealand White (NZW)) F1 strain [1,10,11] and the BXSB strain [12], and in human SLE [1–3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcγRII on macrophages and activated B cells and with hyperactive macrophages resembling those of FcγRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.