Background: Cytokines are a heterogeneous group of molecules organizing different processes of the immune response. Interleukin -4 (IL-4) modulates various immune functions. It plays a vital role in the development of systemic lupus erythematosus (SLE). We aimed to explore the correlation of IL-4 C-589T (rs2243250) gene polymorphism with SLE and its association with disease activity. Method: This study included 100 SLE patients and 90 healthy controls. Disease activity was evaluated by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Samples from all participants were analyzed for IL-4 589 genotyping by restriction fragment length polymorphism (RFLP) and serum IL-4 level by enzyme linked immunosorbent assay (ELISA). Results: IL-4 serum level was significantly lower in patients with SLE (3.14±0.782pg/ml) compared to control (13.82±4.85 pg/ml) (p < 0.001), there was a significant negative correlation between IL-4 serum level and SLEDAI score. CT genotype distribution was significantly lower in SLE patients than controls [OR (95% CI) 0.209 (0.035- 1.246), P < 0.05*]. Regarding the TT genotype distribution, the frequency was higher in SLE compared to the control group but did not reach significant differences [OR (95% CI) 0.866 (0.152- 4.921), P=0.85717]. The frequency of the IL-4 589 T allele was 87% (174 out of 200) in the SLE group compared to 73.9% (133 out of 180) in the controls [OR (2.365 (1.392-4.016), P< 0.01. Conclusion: CT genotype and T allele of IL-4 C-589T (rs2243250) gene can be a risk factor for SLE. Serum IL-4 level significantly correlated with SLEDAI score