Aim To evaluate the efficacy and safty of combination therapy with atorvastatin and fenofibrate in rats with mixed hyperlipidemia. Methods 60 Wistar rats were randomized into normal group, control group, atorvastatin group, AFH group and AFF group. The groups were fed with high fatty foods, except Normal group fed with common foods. At the end of the fourth week, Atorvastatin group [Atorvastatin 1.8 mg/(kg·d)], AFH group [Atorvastatin 0.9 mg/(kg·d)+ Fenofibrate 18 mg/(kg·d), together], and AFF group [Atorvastatin 0.9 mg/(kg·d) + Fenofibrate 18 mg/(kg·d), respectively] were administrated drugs. TC, TG, LDLC, HDLC, ALT, AST and hs-CRP were measured at the end of the fourth and the eighth week. Results The level of TC, LDLC, TG in normal group, atorvastatin group, AFH group and AFF group were obviously lower than control group (P<0.01); That of HDLC in AFH group and AFF group were higher than atorvastatin group(P<0.01). The level of hsCRP in control group, atorvastatin group, AFH group and AFF group were obviously increased than normal group(P<0.05). Compared with Atorvastatin group, the level of hsCRP in AFH group and AFF group were lower. 3.The level of ALT and AST in control group, atorvastatin group, AFH group and AFF group were obviously higher than normal group (P<0.01). Those in Atorvastatin group and AFF group were lower than Control group(P<0.01) and AFH group(P<0.05). Conclusions Combination therapy of fenofibrate plus atorvastatin can strengthen the effects on decreasing lipids and the level of hs-CRP. The negative effects of combination therapy are related to the doses of fenofibrate and atorvastatin, so administrating drugs from low doses and at different time are very important to reduce hepatic damage.