Abstract： Objective To investigate the effect of mycophenolate mofetil (MMF) on the expression of p38 mitogen- activated protein kinase (MAPK) signal pathway in protein- overload nephrotic rats. Methods Thirty SD rats were divided into three groups (n=10 each): control group (normal saline), BSA group [protein-overload nephrotic rats, bovine serum albumin (BSA) group] and treatment group (BSA+ MMF). The protein-overload nephrotic rats were used. After 4 weeks, urinary proteins in 24 h, blood urea nitrogen (BUN) and serum creatinine were measured. Immunhistochemistry was applied to measure the expression of NF-κB. The activity of NF-κB was determined by electrophoretic mobility shift assay (EMSA). Western blot was performed to determine p38 MAPK protein. Renal tissues were examined by light microscopy and electron microscopy. Results The histological changes of BSA group showed tubular atrophy, widening of intertubular spaces with increased lymphocytes and mononuelear cells infiltration and fibrosis. Such histological changes were obriously improved in treatment group. Compared with the control group, urinary protein [(48.3±3.3) mg/24 h vs (67.8±4.5)mg/24 h, P<0.05], expression of NF-κB and p38 MAPK (45.24±6.25 vs 88.59±7.43; 80.68±8.34 vs 235.23±10.41) were significantly increased in protein-overload nephrotic rats (P<0.05). There were positive correlations of p38 MAPK with NF-κB and urinary protein (r=0.72, r=0.65, P<0.05). Compared with BSA group, MMF inhibited the expression of p38 MAPK, NF-κB and partly decreased the level of urinary protein [(59.1±4.2) mg/24 h,P<0.05]. Conclusion MMF can inhibit the expression of NF-κB and its mechanism may be due to the inhibition of p38 MAPK phosphorylation.