Background: Open abdomen (OA) is a surgical option that can be used in patients with severe peritonitis. Few evidences exist to recommend the use of intraperitoneal fluid instillation associated with OA in managing septic abdomen. Materials and methods: A prospective analysis of adult patients enrolled in the International Register of Open Abdomen (trial registration: NCT02382770) was performed. Results: A total of 387 patients were enrolled in two groups: 84 with peritoneal fluid instillation (FI) and 303 without (NFI). The groups were homogeneous for baseline characteristics. Overall complications were 92.9% in FI and 86.3% in NFI (p = 0.106). Complications during OA were 72.6% in FI and 59.9% in NFI (p = 0.034). Complications after definitive closure were 70.8% in FI and 61.1% in NFI (p = 0.133). Entero-atmospheric fistula was 13.1% in FI and 12% in NFI (p = 0.828). Fascial closure was 78.6% in FI and 63.7% in NFI (p = 0.02). Analysis of FI in negative pressure wound therapy (NPWT) showed: Overall morbidity in NPWT was 94% and in non-NPWT 91.2% (p = 0.622) and morbidity during OA was 68% and 79.4% (p = 0.25), respectively. Definitive fascial closure in NPWT was 87.8% and 96.8% in non-NPWT (p = 0.173). Overall mortality was 40% in NPWT and 29.4% in non-NPWT (p = 0.32) and morality during OA period was 18% and 8.8% (p = 0.238), respectively. Conclusion: We found intraperitoneal fluid instillation during open abdomen in peritonitic patients to increase the complication rate during the open abdomen period, with no impact on mortality, entero-atmospheric fistula rate and opening time. Fascial closure rate is increased by instillation. Fluid instillation is feasible even when associated with nonnegative pressure temporary abdominal closure techniques.