Objectives: Although various studies have been performed on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN-MDSCs in the pathogenesis of RA and its specific mechanisms. Methods: We detected the frequencies and counts of PMN-MDSCs, TNF- ⁺ B cells, and Ki67 ⁺ B cells in spleens and inflamed joints of collagen-induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN-MDSCs was examined by anti-Ly6G neutralizing antibodies against PMN-MDSCs or adoptive transfer of PMN-MDSCs. And the modulation of PMN-MDSCs on B cells was conducted by coculture assays, RNA-Seq, RT-qPCR, etc. The mechanism of BAFF regulating B cells was verified through Western Blot and flow cytometry. Results: PMN-MDSCs accumulated in the spleens and joints of CIA mice. PMN-MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF- secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN-MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF- expression, proliferation and apoptosis of B cells in vitro. What’s more, BAFF promoted phosphorylation of BTK/NF-B signaling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF- expression. Conclusions: Our study suggested that PMN-MDSCs enhanced disease severity of CIA and manipulated TNF- expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF- expression through BTK/NF-B signaling pathway, which demonstrated a novel pathogenesis of PMN-MDSC in CIA.