Soluble guanylyl cyclase (sGC) is associated to endothelial barrier dysfunction and inflammatory reaction during acute pancreatitis. Thus, sGC/cGMP inhibition using methylene blue (MB) was investigated. Acute necrotizing pancreatitis was induced by retrograde infusion of sodium taurocholate 5% (1mL/kg) and enterokinase (8U/kg) in the pig pancreatic duct. Pigs were allocated in 4 groups (n=5): 1: control; 2: pancreatitis; 3: MB infusion post pancreatitis; and 4: MB infusion pre pancreatitis. Data underwent Two and One Way Analysis of Variance (ANOVA) followed by Tukey test with p<0.05. Hemodynamic changes begin 3 h after pancreatitis onset and exhibited mild alterations for either MB administrations. Plasma and ascitic amylase and lipase levels were greatly increased in groups 2, 3 and 4. Plasma nitric oxide (NO) was unaltered. Intra‐abdominal fluid collection had a 15‐fold volume increase on group 2. Groups 3 and 4 had less fluid accumulation. Preemptive MB was associated to 50% more free radical injury. For post‐treatment, neutrophil in pancreatic tissue had a 2‐fold increase. In summary, sGC inhibition by MB clinically did not affect hemodynamic pattern due to a non‐pivotal role of NO on this investigation. Moreover, early and late sGC inhibition may worsen free radical damage and magnitude of inflammatory process, respectively. Support: CAPES; FAEPA‐HC/FMRP.