Objective: To investigate the clinical efficacy of double-filtration plasmapheresis (DFPP) in treatment of hyperlipidemic severe acute pancreatitis (HL-SAP). Methods: Fifty-one HL-SAP patients were randomly designated to observational group (26 cases) and control group (25 cases). Patients in control group received standard routine treatment, while those in observational group underwent DFPP in addition to receiving routine treatment protocol. The treatment efficacy variables on day 2 and 7 of treatment and incidence of complications between the two groups were compared. Results: On day 2 of treatment compared with pretreatment values, the triglyceride (TG) and serum and urine amylase levels were significantly reduced, most of the hemorheological parameters were significantly improved, levels of inflammatory factors were lessened while prealbumin was elevated significantly, and the SIRS, APACHE II and Ranson’s scores were significantly decreased in observational group (all P<0.05); in control group, except for Ranson’s score that was significantly decreased (P<0.05), all the other parameters showed no significant change (all P>0.05). On day 7 of treatment, all the above parameters in observational group were further improved, and most of them in control group were significantly improved compared with pretreatment values (all P<0.05). In comparison, at the same time point after treatment, the degrees of improvement of all the parameters in observational group were significantly greater than those in control group (all P<0.05). The incidence of complications in observational group was significantly lower than that in control group (P<0.05). Conclusion: DFPP can effectively decrease TG level, improve microcirculation, and maintain the balance between anti-inflammatory and proinflammatory responses, and thereby improve the prognosis of HL-SAP patients.