Objectives: We observe the effect of ulinastatin on the mRNA and protein expression of chemotactic factor CXCL12 and its receptor CXCR4 in brain tissue of SLE mice with secondary lupus encephalopathy, and we preliminarily investigated the protective effect of ulinastatin on the neurological function of this mouse model. Methods: Ninety SLE mice were divided into three groups: blank control group (normal saline injected i.p.); ulinastatin group (ulinastatin injected i.p.); prednisone group (prednisone injected i.p.). Mouse serum was collected at the intermediate phase (the second month) and final phase (the fourth month) of medicine intervention for detection of cytokines (TNF-alpha and TGF-beta) by ELISA. Mice were sacrificed after four-month drug intervention and brain tissue was harvested for pathological analysis. Apoptosis was detected by TUNEL method. The mRNA and protein expression levels of CXCL12 and its receptor CXCR4 were analyzed by RT-PCR and Western blot, respectively. The mortality of each group was analyzed before sacrifice. Results: Ulinastatin relieved cerebral bleeding, inflammation, edema, etc., and improved memory of model mice. Ulinastatin down-regulated the expression levels of CXCL12 and its receptor CXCR4 in brain tissue, down-regulated serum TNF-alpha, up-regulated serum TGF-beta and reduced neuronic apoptosis. Moreover, ulinastatin significantly decreased the mortality of mice compared with the prednisone and blank control group. Conclusions: Ulinastatin affects the progression of secondary lupus encephalopathy and exerts protective effects on the neurological function of CNS-SLE mice. The regulation of the expression levels of CXCL12 and its receptor CXCR4 may be one of the mechanisms.