Background: Sequence variation in gene promoters is often associated with disease risk. In this study, we tested the hypothesis that common promoter variation in the APOM gene is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Chinese cohort. Meanwhile, we investigated the expression of apolipoprotein M (APOM) in the serum of patients with systemic lupus erythematosus (SLE) and its relationship with disease activity. Methods: We used a case-control design and genotyped 52 SLE patients and 52 healthy controls for 19 APOM promoter single nucleotide polymorphism (SNP) (rs113947529, rs1143030, rs114826514, rs116715239, rs12525463, rs1266078, rs2273612, rs28432254, rs34490746, rs4947251, rs55880811, rs707921, rs74890500, rs75629491, rs76611345, rs76794541, rs805264, rs805297, rs9267528). Genotyping was done by matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF MS). The blood serum concentration of APOM was measured by an enzyme-linked immunosorbent assay in SLE patients and controls. Results: The average concentration of APOM in serum was significantly lower in SLE patients compared to controls and APOM levels in SLE patients with positive anti-dsDNA antibodies were dramatically lower than that of patients with negative anti-dsDNA antibodies (P = 0.011). It was interesting that APOM levels correlated with systemic lupus erythematosus disease activity index (SLEDAI) scores (r = -0.396, P = 0.004). No association between APOM and SLE susceptibility was detected in our Han Chinese cohort. Conclusions: Our results demonstrated that lower APOM levels in SLE patients and correlated with disease activity.