Systemic lupus erythematosus (SLE) is an autoimmune disease of complicated and multifactorial pathogenesis. Interleukin 33 (IL-33) may play a role in the development of SLE through upregulation of toll like receptor 4 (TLR-4). The objective of this study was to investigate the association of IL- 33 serum levels and relative expression of TLR 4 with SLE development and clinical outcome. This case-control study included 80 SLE patients and 80 normal controls. Ribonucleic acid (RNA) was extracted from peripheral blood mononuclear cells. The serum level of IL 33 was measured by the enzyme linked immunosorbent assay (ELISA) and relative expression of TLR-4 determined by real time polymerase chain reaction. Clinical findings and SLE activity were evaluated for all patients. IL-33 serum levels and relative expression of TLR-4 were significantly higher in SLE patients when compared with controls (p<0.001). There were statistically significant differences in the mean IL-33 serum levels and mRNA expression of TLR 4 among disease activity groups. They were proportionally increased with SLE activity where the highest concentrations existed in the highest disease activity patients (p< 0.001). A positive correlation was found between IL-33 serum levels and mRNA expression of TLR-4 in SLE patients (r=0.86 and p≤0.001). In conclusion, elevated IL-33 serum levels inducing increased expression of TLR-4 could be constituted as an important factor in the pathogenesis and activity of SLE.