This paper reviewed our experience with the nonsurgical management of acute necrotizing pancreatitis (ANP) by continuous regional arterial infusion (CRAI) of protease inhibitor (nafamostat mesilate, 240 mg/day) and antibiotic (imipenem, 0.5 g every 12 h). 47 patients with ANP admitted within 7 days were treated with intensive care and CRAI for 5 days prospectively. 40 patients responded to CRAI therapy and the mortality rate in these patients was 2.5%. 7 patients (14. 9%) did not respond to CRAI. 5 of 7 nonresponders died of multiple organ failure although pancreatic necrosis was persistently sterile. The remaining 2 patients who underwent necrosectomy for infected pancreatic necrosis recovered after surgery. In 34 patients treated with CRAI in the early stage within 72 h after the onset, 31 (91.2%) responded. The mortality rate was 5.9% and the incidence of infected pancreatic necrosis was 2.9% in these 34 patients. These results demonstrated that most patients with ANP responded to conservative management combined with CRAI with nafamostat and imipenem when employed within 72 h after the onset. Early intervention of CRAI with protease inhibitor and antibiotic has a significant role in the nonsurgical management of ANP.