Objective To study the clinical protective effect of hemoperfusion combined with hemofiltration on inflammatory reaction of hyperlipidemia severe acute pancreatitis (HLSAP). Methods Thirty-seven patients with HLSAP treated between January 2012 and December 2014 were selected and divided into three groups based on different treatments. Thirteen patients were allocated into hemoperfusion combined with continuous veno-venous hemofiltration group (HP+CVVH group) and treated with hemoperfusion combined with hemofiltration; 11 patients were allocated into continuous veno-venous hemofiltration group (CVVH group) and treated with hemofiltration; and all the other patients were allocated into control group and treated with conventional treatment. The levels of blood triglyceride, C-reactive protein, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8) and acute physiology and chronic health evaluation (APACHE)Ⅱ score of the patients after treatment were observed. The hospital stay, organ dysfunction rate and mortality of the patients were measured. Results Compared with the control group, the levels of blood triglyceride, C-reactive protein, TNF-α, IL-6, IL-8 and APACHE Ⅱ score of the patients in the HP+CVVH group and CVVH group were both significantly reduced 72 hours after therapy (P<0.05). However, the levels of blood triglyceride, C-reactive protein, TNF-α, IL-6, IL-8 and APACHE Ⅱ score of the patients in the HP+CVVH group were significantly lower than those in the CVVH group at the same time point (P<0.05). The hospital stay of the patients in the HP+CVVH group and CVVH group was significantly shorter than that in the control group (P<0.05). Compared with the CVVH group, the hospital stay of patients in the HP+CVVH group was significantly shorter (P<0.05). There was no statistical difference in organ dysfunction rate and mortality among the three groups (P>0.05). Conclusion Hemoperfusion combined with hemofiltration is an effective method for HLSAP by cleaning the inflammatory mediators availably and inhibiting the excessive inflammatory reaction.