Continuous renal replacement therapy (CRRT) showed promising results in the management of critically ill patients with systemic inflammatory response syndrome (SIRS)/sepsis. However, the underlying mechanism is still not very clear. A change of immune homeostasis in critically ill patients during CRRT was observed only to a smaller degree. The purpose of this study was to test the hypothesis that high-volume continuous venovenous hemofiltration (HV-CVVH) treatment could improve monocyte function and restore immune homeostasis in patients with severe acute pancreatitis (SAP). This was a prospective clinical trial in the surgical intensive care unit of a teaching hospital. Subjects were 16 patients with severe acute pancreatitis: sepsis group (n=7): positive culture result and in the late phase of disease (from onset of SAP to receiving CVVH therapy: more than 3 days); and nonseptic group (n=9): negative culture result and early phase of disease (less than 3 days). Patients received 72 hours of HV-CVVH. We measured the change in mean arterial pressure, APACHE II score, monocyte functions (including antigen-presenting and cytokine production ability), and plasma cytokines. Mean arterial pressure were stable accompanied with APACHE II score improvements. HLA-DR expression on monocytes (antigen-presenting ability) were markedly decreased (p<0.0001) in all patients. Lipopolysaccharide (LPS)-induced TNF-alpha, interleukin-6 (IL-6), and IL-10 production from patients' monocytes markedly decreased in septic patients, but significantly increased in nonseptic patients. During HV-CVVH treatment, HLA-DR expression was markedly increased in nonseptic patients in 24 hours (p<0.05), and in septic patients in 72 hours (p<0.05). LPS-induced cytokine production was decreased in nonseptic patients, but not significantly changed in septic patients. The change of plasma cytokines showed the same trend. In patients with SAP, HV-CVVH was associated with improved hemodynamics. HV-CVVH restores monocytes functions, especially in patients in the early phase of the disease and without sepsis. These findings suggest a potential role for HV-CVVH in the treatment of SAP.