Systemic lupus erythematosus is characterized by profound changes of the immune system. We report on alterations of the macrophage system in the murine NZB/W model of this disease. A greatly increased number of mature macrophages was isolated from the liver of NZB/W mice as compared to BALB/c mice and several other inbred strains used as healthy controls. In addition, the macrophage precursor compartment in the liver of NZB/W mice was expanded severalfold as measured by proliferation of light-fraction nonadherent nonparenchymal cells (NPCs) in response to colony-stimulating factors. Functional properties of the macrophages isolated from various anatomic sites of the lupus-prone mice were tested. Production of monokines by macrophages from liver, spleen, and peritoneal cavity, calculated on a per cell basis, was in the same range as in several healthy control strains tested. Yet the overall production of these immunoregulatory molecules by the increased liver macrophage system, the body's largest compartment of macrophages, is likely to result in increased levels of circulating monokines in the plasma of lupus-prone NZB/W mice. Indeed, significantly elevated levels of interleukin-6, interleukin-1, and colony-stimulating activity could be demonstrated in the plasma of these mice both spontaneously and after stimulation with lipopolysaccharide. A possible contribution of the expansion of the macrophage system to the development of the disease is discussed.