BACKGROUND Anastomotic leakage (AL) is a severe complication associated with high morbidity and mortality after radical gastrectomy (RG) for gastric cancer (GC). We hypothesized that a novel abdominal negative pressure lavage-drainage system (ANPLDS) can effectively reduce the failure-to-rescue (FTR) and the risk of reoperation, and it is a feasible management for AL. AIM To report our institution's experience with a novel ANPLDS for AL after RG for GC. METHODS The study enrolled 4173 patients who underwent R0 resection for GC at our institution between June 2009 and December 2016. ANPLDS was routinely used for patients with AL after January 2014. Characterization of patients who underwent R0 resection was compared between different study periods. AL rates and postoperative outcome among patients with AL were compared before and after the ANPLDS therapy. We used multivariate analyses to evaluate clinicopathological and perioperative factors for associations with AL and FTR after AL. RESULTS AL occurred in 83 (83/4173, 2%) patients, leading to 7 deaths. The mean time of occurrence of AL was 5.6 days. The AL rate was similar before (2009-2013, period 1) and after (2014-2016, period 2) the implementation of the ANPLDS therapy (1.7% vs 2.3%, P = 0.121). Age and malnourishment were independently associated with AL. The FTR rate and abdominal bleeding rate after AL occurred were respectively 8.4% and 9.6% for the entire period; however, compared with period 1, this significantly decreased during period 2 (16.2% vs 2.2%, P = 0.041; 18.9% vs 2.2%, P = 0.020, respectively). Moreover, the reoperation rate was also reduced in period 2, although this result was not statistically significant (13.5% vs 2.2%, P = 0.084). Additionally, only ANPLDS therapy was an independent protective factor for FTR after AL (P = 0.04). CONCLUSION Our experience demonstrates that ANPLDS is a feasible management for AL after RG for GC.