Objectives: Toll-like receptor 7 (TLR7) can sense single-stranded RNA with subsequent induction of different interferon (IFN) types including IFN lambda (IFNL) and may contribute to autoimmune diseases. The present work was designed to investigate the potential role of TLR7 and IFNL1 in systemic lupus erythematosus (SLE) in relation to disease activity and development of lupus nephritis (LN).   Methods: Thirty patients with SLE (15 patients without LN and 15 patients with histologically-proven LN) and 15 healthy controls were enrolled in the study. Disease activity was assessed using SLE disease activity index (SLEDAI). TLR7 expression on peripheral blood CD14+ monocytes was studied by color flow cytometry. IFNL1 levels in serum were quantified using enzyme-linked immunosorbent assay. Renal function was assessed by estimating serum creatinine, estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine (UAC) ratio.  Results: The number of peripheral blood CD14+ TLR7+ monocytes and serum IFNL1 levels showed significant increases in patients with and without LN compared with healthy controls and in patients with LN compared with those without LN (P < 0.001). Changes in TLR7 expression and IFNL1 levels in peripheral blood were positively correlated (P < 0.001) and both showed positive correlations with SLEDAI score, erythrocyte sedimentation rate, high-sensitivity C-reactive protein, serum creatinine, UAC ratio, and renal activity index and inverse correlations with eGFR and serum complement 3 and 4 in SLE patients (P < 0.05). The receiver operating characteristic curve analysis showed high sensitivity and specificity of the number of peripheral blood CD14+ TLR7+ monocytes in discriminating patients with and without LN (100% and 93.33% respectively, area under the curve = 0.996, P<0.001). Conclusions: Activation of TLR7/IFNL1 pathway may play an important role in the pathogenesis of SLE in relation to disease activity and development of LN and could be a potential therapeutic target for the treatment of SLE and LN.