To investigate the effect of the clinical effective prescription of Qingre Lishi Yishen decoction (QRLS) on the activation of mesangial cells in immunoglobulin A nephropathy (IgAN) rats. IgAN rat's model was established by combine with intragastric administration of bovine serum albumin (BSA) + intravenous injection of lipopolysaccharide (LPS) by + subcutaneous injection of carbon tetrachloride (CCL4). Then the animals were randomly divided into four groups: control group, IgAN model group, IgAN model with Valsartan (Val) treatment group and IgAN model with QRLS treatment group. To observe the indexes of 24-h urine protein, renal function, deposition of immune complexes, expression of activation factor, fibrosis marker and inflammatory cytokines in four different groups. The Val or QRLS treatment group: (a) it reduced the immune complexes deposition of IgA in glomerular mesangial and inhibited mesangial cell proliferation; (b) it decreased the expression of smooth muscle actin (α-SMA), fibronectin (FN) and tumor necrosis factor alpha (TNF-α). The study suggested that QRLS ameliorate renal structure and function in IgAN rat's model. Furthermore, we also observed that QRLS alleviated mesangial cells activation and matrix accumulation partly by decreasing the α-SMA, then to downregu.