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DNASE1L3 is an extracellular nuclease that digests chromatin released from apoptotic cells. DNASE1L3variants impair the enzyme function, enhance autoantibody production and type I interferon (IFN-I) responses, and cause different autosomal recessive phenotypes ranging from hypocomplementemic urticarial vasculitis syndrome to full-blown systemic lupus erythematosus (SLE). Kidney involvement in patients with DNASE1L3variants is poorly characterized. Herein, we describe the clinical course of 3 children with monogenic SLE due to DNASE1L3variants who developed refractory glomerulonephritis leading to kidney failure. They had different renal histopathological patterns (ie, membranous, endocapillary, and extracapillary glomerulonephritis and thrombotic microangiopathy), all belonging to the lupus nephritis (LN) spectrum. One patient had a mixed phenotype, showing an overlap between SLE and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Using immunofluorescence, we detected glomerular expression of the IFN-I–induced human myxovirus resistance protein 1 (MXA), which was particularly evident in glomerular endothelial cells. Two of the patients had increased expression of interferon-stimulated genes in the peripheral blood, and all 3 patients had reduced serum DNAse activity. Our findings suggest that DNASE1L3-related glomerulonephritis can be included in the spectrum of IFN-I–mediated kidney disorders and provide the rationale for IFN-I–directed therapies in order to improve the poor outcome of this rare condition.