Objective. Alterations in the function of dendritic cells (DCs) may explain the systemic autoimmune responses that characterize systemic lupus erythematosus (SLE). Even though several reports have documented the beneficial effect of intravenous immunoglobulin (MG) in SLE, the underlying mechanisms of action remain poorly understood. Considering the effect of serum factors, including interferon-α (IFNα), on the activity of DCs, we investigated the effects of MG on the differentiation of DCs mediated by serum from SLE patients. Methods. DCs were differentiated from peripheral blood monocytes obtained from SLE patients and from healthy blood donors, in the presence of SLE serum. MG was used at a concentration of 0.15 mM. A functional assay was performed to assess the inhibitory effect of MG on the uptake of nucleosomes by DCs. Results. MG interfered with the differentiation of DCs from SLE patients and healthy donors cultured in the presence of SLE serum. Treatment of DCs with MG inhibited the ingestion of nucleosomes by immature DCs, by up to 36%. Conclusion. The present findings indicate that MG, by down-regulating the IFNα-mediated differentiation of DCs and by inhibiting uptake of nucleosomes, may exert an essential immunoregulatory effect in SLE patients at the onset of the immune response, at the DC level. Given the critical role of HLA molecules and the costimulatory signals delivered by CD80 and CD86 in optimal antigen presentation and T cell activation, inhibition of expression of HLA and CD80/CD86 on DCs by MG offers a plausible explanation for the efficacy of MG in SLE and other immune-mediated inflammatory conditions.