Renal infiltration with mononuclear cells is associated with poor prognosis in systemic lupus erythematosus. A renal macrophage/dendritic cell signature is associated with the onset of nephritis in NZB/W mice, and immune-modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. In nephritic NZB/W mice, renal F4/80 hi/CD11c int macrophages are located throughout the interstitium, whereas F4/80 lo/CD11c hi dendritic cells accumulate in perivascular lymphoid aggregates. We show here that F4/80 hi/CD11c int renal macrophages have a Gr1 lo/Ly6C lo/VLA4 lo/MHCII hi/CD43 lo/CD62L lo phenotype different from that described for inflammatory macrophages. At nephritis onset, F4/80 hi/CD11c int cells upregulate cell surface CD11b, acquire cathepsin and matrix metalloproteinase activity, and accumulate large numbers of autophagocytic vacuoles; these changes reverse after the induction of remission. Latex bead labeling of peripheral blood Gr1 lo monocytes indicates that these are the source of F4/80 hi/CD11c int macrophages. CD11c hi/MHCII lo dendritic cells are found in the kidneys only after proteinuria onset, turnover rapidly, and disappear rapidly after remission induction. Gene expression profiling of the F4/80 hi/CD11c int population displays increased expression of proinflammatory, regulatory, and tissue repair/degradation-associated genes at nephritis onset that reverses with remission induction. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling.