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Objectives Immunoglobulin M (IgM) to oxidation-specific epitopes (OSE), predominantly natural antibodies, is induced by oxidative mechanisms. Higher IgM to OSE has been associated with reduced cardiovascular risk, whereas impaired IgM production has been reported in systemic lupus erythematosus (SLE).Methods Serum samples from 137 SLE patients, 135 rheumatoid arthritis (RA) patients, and 135 healthy controls (HCs) were analyzed for IgM to MDA-LDL, oxidized LDL, phosphorylcholine-modified BSA (PC-BSA), apoB100 immune complexes (ICs), and the P1-peptide mimotope using ELISA.Results IgM to MDA was reduced in SLE compared to HCs (p < 0.001) and RA (p = 0.002). PC-BSA and oxidized LDL IgM levels were similarly decreased in SLE versus HCs (both p < 0.001) but not versus RA. ApoB100 IC IgM was lower in SLE than HCs (p < 0.001). In contrast, P1-peptide IgM was higher in SLE compared to HCs (p = 0.008) and RA (p < 0.001). MDA IgM correlated inversely with hemoglobin and complement 3. PC-BSA IgM was negatively associated with hematologic involvement, hemoglobin, C3, and positively with SLEDAI. Oxidized LDL IgM correlated with renal and hematologic involvement, hemoglobin, anti-dsDNA, C3, C4, SLEDAI, proteinuria, and glucocorticoid dose. ApoB100 IC IgM was associated with renal and hematologic involvement, decreased C3, increased SLEDAI and proteinuria, and glucocorticoid dose. P1-peptide IgM correlated inversely with C3 and positively with SLEDAI.Conclusions SLE patients demonstrated reduced natural IgM to multiple OSEs, whereas IgM to the P1 mimotope was elevated. IgM responses to oxidized LDL and apoB100 ICs were associated with disease activity and organ involvement, indicating selective dysregulation of OSE-specific humoral immunity in SLE.