Systemic lupus erythematosus is an autoimmune disease, characterized by high liters of autoantibodies against many cell‐membrane and intracellular antigens. Polyclonal B cell activation and alterations in the T cell compartment have been described. The present report deals with the organ‐associated macrophage (MΦ) system of two lupus‐prone mouse strains (NZB/W and MRL lpr/lpr) and demonstrates that in both mouse strains the MΦ compartment of liver and spleen is clearly expanded. In the liver the number of F 4/80⁺ MΦ is strongly elevated. In addition, presence of early MΦ precursors and of extramedullary organassociated monocyte proliferation in response to colony‐stimulating factor (CSF) is documented in liver and spleen of these mice. Further, in normal animals during the first two weeks of life extramedullar monocytopoiesis is present in liver and spleen, which is then down‐regulated in the third week of life. In the two lupus‐prone mouse strains down‐regulation does not occur but extramedullar monocyte proliferation is sustained at high level throughout life time. As possible correlates for the expansion of the MΦ system elevated CSF‐1 mRNA levels are demonstrated in kidney, spleen and liver of NZB/W mice and elevated CSF serum levels are documented in MRL lpr/lpr mice. The possible contribution of the expanded MΦ system to B and T cell dysregulation is discussed.