Background and purpose: To investigate the role of bromodomain-containing protein 4 (Brd4) in regulating B cell differentiation and its therapeutic potential for B cell-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Experimental Approach: Human and murine B cells were purified and cultured with different stimuli. B cell surface markers, proliferation and apoptosis were estimated by flow cytometry. Gene expression was measured by quantitative real-time PCR. Brd4 binding sites were analysed by the luciferase reporter assay and the chromatin immunoprecipitation (ChIP) assay. PFI-1 or JQ1 was used to inhibit Brd4. Mice with B cell-specific deletion of the Brd4 gene (Brd4flox/floxCD19-Cre+/-) and MRL/lpr mice were used to perform the in vivo experiments. Key Results: Brd4 inhibition suppressed plasmablast-mediated plasma cell differentiation but did not influence proliferation or apoptosis in healthy human and murine CD19+ B cells. PFI-1 treatment reduced the secretion of IgG and IgM in the supernatants of costimulation-induced B cells. Mechanistically, Brd4 regulates the terminal differentiation of B cells into plasma cells by targeting BLIMP1 by directly binding and activating the endogenous BLIMP1 promoter. Interestingly, PFI-1 treatment decreased the percentages of plasmablasts and plasma cells from patients with SLE. PFI-1 administration reduced the percentages of plasma cells, hypergammaglobulinemia and attenuated nephritis in MRL/lpr mice. Pristane-injected Brd4flox/floxCD19-Cre+/- mice exhibited improved nephritis and reduced percentages of plasma cells. Conclusions and Implications: Brd4 is an essential factor in regulating plasma cell differentiation. Brd4 inhibition may be a potential new strategy for the treatment of B cell-associated autoimmune disorders, including SLE.