To investigate the efficacy of continuous regional arterial infusion (CRAI) of a protease inhibitor and antibiotic for severe acute pancreatitis (SAP) in patients admitted to an intensive care unit (ICU). A total of 51 patients with SAP requiring admission to an ICU were studied. The patients were divided into two groups: one received the protease inhibitor nafamostat mesylate and the antibiotic imipenem by continuous regional arterial infusion (CRAI group) and the other received protease inhibitors and antibiotics by intravenous infusion (non-CRAI group). To evaluate the therapeutic usefulness of CRAI of a protease inhibitor and antibiotic for SAP, the rate of surgery and the cumulative survival rate were compared between the non-CRAI group and the CRAI group. The rate of surgery was 32% in the non-CRAI group and 9% in the CRAI group (P = 0.08). Cumulative survival rates at 1, 6, and 12 months were 77.9%, 48.9%, and 48.9% in the non-CRAI group compared with 100.0%, 100.0%, and 87.1% in the CRAI group. Outcome was thus significantly better in the CRAI group than in the non-CRAI group (P = 0.002). CRAI of a protease inhibitor and antibiotic may decrease the need for surgical therapy and reduce mortality in patients with SAP.