The present study aimed to examine the effects of FcγRIIB on systemic lupus erythematosus (SLE) and to investigate the underlying mechanisms. For this purpose, lentiviral vector carrying the membrane‑bound type FcγRIIB gene (mFcγRIIB lentivirus) and soluble FcγRIIB (sFcγRIIB) protein were used to treat B cells from patients with SLE. The B cells were treated with calf thymus DNA (ctDNA) and anti‑calf thymus DNA‑immune complexes (anti‑ctDNA‑IC). mFcγRIIB lentivirus and sFcγRIIB protein were also injected into MRL/lpr SLE mice. The results revealed that anti‑ctDNA‑IC treatment significantly downregulated the IgG antibody secretion of B cells treated with mFcγRIIB lentivirus. mFcγRIIB and sFcγRIIB decreased the phosphorylation level of Bruton's tyrosine kinase (BTK) in B cells, and increased the phosphorylation level of Lyn proto‑oncogene (Lyn), docking protein 1 (DOK1) and inositol polyphosphate‑5‑phosphatase D (SHIP). mFcγRIIB promoted the apoptosis of B cells. Following the treatment of MRL/lpr SLE mice with mFcγRIIB lentivirus, the levels of urinary protein, serum anti‑nuclear and anti‑dsDNA antibodies were decreased, while the levels of mFcγRIIB in B cells were increased. mFcγRIIB ameliorated the pathologies of the kidneys, liver and lymph node tissues of the MRL/lpr SLE mice. Following treatment of the MRL/lpr SLE mice with sFcγRIIB, the levels of urinary protein, serum anti‑dsDNA antibody and BTK and SHIP phosphorylation levels in B cells were decreased, while the serum sFcγRIIB and sFcγRIIB‑IgG levels were increased. On the whole, the findings of the present study demonstrate that recombinant FcγRIIB inhibits the secretion of IgG antibody by B cells from patients with SLE, ameliorates the symptoms of SLE in mice, and alters the phosphorylation levels of downstream proteins of the FcγRIIB signaling pathway in B cells. These results suggest that FcγRIIB may play preventive and therapeutic roles in SLE by inhibiting B cell activation via the FcγRIIB signaling pathway, which provides a novel theory and strategy for the prevention and treatment of SLE.