Objective: To investigate the effect of pidotimod on proteinuria and renal tissues in rats with Henoch-Schonlein purpura nephritis (HSPN). Methods: Of 40 Sprague Dawley (SD) rats, 10 rats were selected as control group, and the remaining 30 rats were treated with bovine serum albumin (BSA) + lipopolysaccharide (LPS) + carbon tetrachloride (CCl4) to establish rat with HSPN model. Twenty-eight rats with HSPN were divided into model group and pidotimod group. Pidotimod group was i.p. injected with 10 mg/kg of pidotimod, while model and control groups were i.p. injected with the same amount of normal saline (once/d). The treatment lasted for 28 consecutive days. On the 7th, 14th, and 28th days of administration, the levels of 24-h proteinuria were measured in each group. After the last administration, conventional hematoxylin-eosin (HE) staining and periodic acid Schiff (PAS) staining were performed to observe the histol. alterations of the kidneys in each group. ELISA (ELISA) was applied to detect the levels of interleukin-4 (IL-4) and IL-1β in renal tissues. Western blot was used to detect the protein expression levels of transforming growth factor β1 (TGF-β1), Smad homolog 4 (Smad4) and Smad7 in renal tissues. Results: On the 7th, 14th, and 28th days, the level of 24-h proteinuria was in model group > pidotimod group > control group (P<0.05). HE staining showed that the pathol. alterations of renal tissues in pidotimod group were less than those in the model group, but still accompanied by a small amount of inflammatory cell infiltration. The gray value of PAS staining pos. area, the protein expression levels of IL-4, IL-1β, TGF-β1, and Smad4 were model group > pidotimod group > control group (P<0.05). Smad7 expression level was model group < pidotimod group < control group (P<0.05). Conclusion: Pidotimod can effectively inhibit proteinuria in rats with HSPN and reduce the pathol. damage of kidney tissue. Its action of mode may be related to the inhibition of inflammation and regulation of TGF-β1/Smad signaling pathway.