Background: Systemic lupus erythematosus (SLE) is a serologically & clinically heterogeneous disorder that is associated with abnormal immune response. β2MG is a low-molecular-weight-protein and is mainly released from immune-related cells including activated T- and B-cells and macrophages. Cystatin C is a low molecular cysteine protease inhibitor secreted by almost all nucleated cells in humans. Objective: The aim of this work was to assess serum β2MG and Cystatin C levels among SLE patients and control subjects and assess their possible correlation with disease activity. Patients and methods: This case control study was conducted on 40 SLE patients and 40 apparently healthy subjects. The SLEDAI-2K was utilized to asses disease activity. Score was graded as: < 3 mild, 3–6 moderate, and > 6 severe. Results: The mean serum β2MG level and Cystatin C level were statistically significantly greater among SLE patients compared with in healthy controls. There was significant correlation between serum β2MG and Cystatin C concentrations and SLEDAI-2k disease activity score. The Receiver Operating Characteristics curve for serum β2MG and serum Cystatin C utilized to differentiate between active and non-active SLE patients with the best detected cut off point were 6.65 and 1.13 yielding sensitivity of 78.3% and 73.9% respectively, specificity of 70.6% and 35.3%, respectively. Conclusion: Serum β2MG concentrations are significantly elevated in SLE patients in comparison with healthy subjects. The sensitivity, specificity and accuracy of β2MG were higher than that of Cystatin C in identifying SLE activity and differentiation between SLE patients and controls.