Objective To investigate the mRNA level of glucocorticoid receptor α (GRα) and heat shock protein 90 (HSP90) in peripheral blood mononuclear cells (PBMCs) and the plasma protein level of macrophage migration inhibitory factor (MIF) in patients with systemic lupus erythematosus (SLE) and to analyze their association with glucocorticoid (GC) resistance.Methods One hundred and six patients with SLE and thirty-eight healthy controls were enrolled in this study.Transcription levels of GRα and HSP90 were determined by real-time polymerase chain reaction.Enzyme-linked immunosorbent assay was used to detect the protein level of plasma MIF.The association between these parameters and GC resistance was analyzed by Spearman correlation analysis.The multivariate logistic regression model was used to analyze the risk factors for GC resistance.Results The mRNA level of GRα and HSP90 in GC resistance group was significantly lower than that in GC sensitive group [10.18(3.12,17.20) vs 16.83(12.01,24.18), P =0.001;18.46(14.77,26.45) vs 25.84 (17.97,35.90), P =0.005].MIF protein level in GC resistance group was significantly higher than that in GC sensitive group [(23.21 ±7.98) μg/L vs (18.34 ±6.29)μg/L;P =0.013].The mRNA level of HSP90 in the high MIF group was significantly lower than that in the low MIF group [23.67 (13.84,28.32) vs 26.64 (23.61,47.16);P =0.001], as well as HSP90/GRαratio(P =0.008).Additionally, the plasma protein level of MIF was negatively correlated with HSP90 (r =-0.275, P =0.004) and HSP90/GRα ratio(r =-0.341, P ＜ 0.001).SLE activity index score in GC resistance group was significantly higher than that in GC sensitive group [(12.23 ±2.86) μg./L vs (9.63 ± 3.48) μg/L;P =0.003].Logistic regression model indicated that disease activity was an independent risk factor for GC resistance (OR =17.481, 95％ CI 1.747-174.903, P =0.015).Conclusions Our preliminary findings suggest that low mRNA level of GRα and HSP90 and high protein level of MIF are associated with GC resistance.Elevated MIF level in SLE patients may play an important role in the development of GC resistance through down-regulating HSP90 and destabilizing the balance of HSP90/ Grα.Disease activity is the risk factor for GC resistance, which might be the viable evidence of therapy response.