Aim To observe the effect of benzafibrate on serum paraoxonase-1 (PON-1) activity in mice during the acute phase response and to investigate the mechanism of anti-oxidation effect. Methods 32 male C57BL/6 mice were randomly divided into 4 groups: in the control group mice were fed with ordinary dietary for 8 weeks; in the benzafibrate group mice were fed with benzafibrate [150 mg/(kg·d)]for 8 weeks; in the lipopolysaccharide (LPS) group mice received intraperitoneal injection of LPS (25 μg) and serum was collected 24 hours later; in the benzafibrate plus LPS group mice were fed with benzafibrate [150 mg/(kg·d)]for 8 weeks and then received an intraperitoneal injection of LPS (25 μg). Serum PON-1 activity was assessed by use of phenylacetate (arylesterase) as substrate and were determined with spectrophotometer. Results Serum PON-1 activity treated with benzafibrate were higher than those in the control group [120.97±39.83 μmol/(min·L) vs 32.71±4.40 μmol/(min·L), P<0.01]. LPS decreased serum PON-1 activity compared with the control group [3.23±0.76 μmol/(min·L) vs 32.71±4.40 μmol/(min·L), P<0.01]. There was no difference between the benzafibrate plus LPS group and the control group. Serum PON-1 activity was positively correlated with high density lipoprotein cholesterol (HDLC) levels (r=0.538, P=0.001). Conclusions Serum PON-1 activity decreased during the acute inflammation phase induced by LPS. Bezafibrate can increase the PON-1 activity, which may be related to its anti-oxidation effect. The effect of benzafibrate may be associated with the increment of HDLC.