Aberrant expression of microRNAs (miRNAs) has been identified in various diseases. Recent studies demonstrated that miRNAs can be detected in the circulation and serve as potential biomarkers of various diseases. Moreover, the detection of circulating miRNAs can provide important novel information concerning diseases. In this study, a miRNA profile was used to determine the aberrantly expressed circulating miRNAs in patients with systemic lupus erythematosus (SLE) compared with patients with rheumatoid arthritis (RA) and healthy controls (HCs). To further confirm the microarray data, we identified 8 miRNAs (miR-126, miR-21, miR-451, miR-223, miR-16, miR-125a-3p, miR-155, and miR-146a) by real-time quantitative PCR (qRT-PCR) in 20 healthy controls and in 55 patients, of whom 30 patients were diagnosed with SLE and 25 were diagnosed with RA. Consistent with the microarray data, miR-126 was specifically enriched only in the blood of the SLE patients, but 4 other miRNAs (miR-21, miR-451, miR-223, and miR-16) were upregulated in the patients with SLE and were also significantly increased in the patients with RA. In contrast, miR-125a-3p, miR-155, and miR-146a showed a trend toward significantly reduced levels in the patients with SLE. In addition, to further estimate the potential roles of these differentially expressed circulating miRNAs in the pathogenesis of SLE, we used a bioinformatics exploratory analysis and identified a number of significantly enriched pathways, which implied that most dysregulated circulating miRNAs might be involved in various signal transduction pathways and cell interactions, particularly the mitogen-activated protein kinase signaling pathway. Based on these findings, we postulate that aberrantly expressed plasma miRNAs could be attractive as candidates for putative biomarkers of SLE and may help elucidate the possible pathogenesis of SLE.