Background and purpose: To investigate the effect of hIgDFc-Ig (DG), a new biological agent that competitively binds to IgD receptors, on collagen-induced arthritis and its potential mechanism in regulating B cell antigen-receptor signaling pathway. Experimental approach: DBA1 mice were used to establish collagen-induced arthritis model, three doses of DG were administered by intraperitoneal injection. Clinical assessment of CIA, histopathological examination, flow cytometry, western blotting, immunofluorescence staining, protein chips and other methods were used to evaluate the therapeutic effects. The effects of DG on Daudi cells and IgαIgβ KO Ramos cells stimulated by IgD were also evaluated. Key results: We found that DG has a significant therapeutic effect on CIA mice. DG relieved the clinical assessment of CIA mice and improved the pathology of joints and spleen. In addition, DG can also regulate B cell subsets in the PBMC and spleen of CIA mice, and decrease the level of immunoglobulins. DG can inhibit the BCR signaling activation stimulated by IgD and effect the expression of transcription factors in vitro. In Ramos cells, Igβ or IgαIgβ knockout may reverse the activation of BCR signal pathway under the stimulation of IgD. Conclusion and Implications: DG may play a therapeutic role in CIA mice by regulating BCR-Lyn-Syk-NF-κB signaling pathway, and may be a new promising biological agent for rheumatoid arthritis.