Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical manifestations mostly affecting the skin, joints, hematopoietic system, kidney, and the central nervous system. The micro-RNAs (miR) are small, non-coding, endogenous RNAs, with key roles in many biological processes. The aim of this study was to investigate the cellular expression of miR-21 and miR-155 in SLE patients and healthy controls. Methods: SLE patients (n=35) and matched healthy controls (n=35) were enrolled in this study. SLE activity was assessed with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. The peripheral blood mononuclear cells (PBMC) were isolated and the RNA was extracted following cDNA synthesis. The expression of miR-21 and miR-155 was evaluated by the real-time PCR technique. Results: The results showed that the expression level of miR-21 was significantly reduced in patients (0.64 times and p-value=0.02) and significantly correlated with disease duration. However, no significant differences were observed between the patients and control subjects for miR-155 (p-value =0.42). Moreover, the expression of miR-21 was indirectly correlated with the disease duration (R= -0.24, p-value = 0.05), but miR-155 did not reveal any significant association with clinicopathological features of the patients. Conclusion: The result of this study suggests a significant down-regulation of miR-21 in PBMC of SLE patient, mostly in individuals with a longer disease history.