Background The majority of patients with symptomatic sterile walled-off necrosis (WON) can be treated conservatively. Although endoscopic transluminal drainage (ETD) is often performed in cases of persistent symptoms, post-procedural iatrogenic infection may occur. This study aimed to evaluate clinical outcomes after ETD of symptomatic sterile WON. Methods This was a retrospective, multicenter, open-label case series of 56 patients with necrotizing pancreatitis who underwent ETD for symptomatic sterile WON between July 2001 and August 2018 at two tertiary referral hospitals. Primary end point was clinically relevant post-procedural iatrogenic infection, defined as need for endoscopic transluminal necrosectomy. Secondary end points included mortality, total number of interventions, hospital stay, and resolution of symptoms at 1-year follow-up. Results ETD of sterile WON was performed in 56 patients (median age 55 years, 57 % male), who presented with abdominal pain (71 %), gastric outlet obstruction (45 %), jaundice (20 %), and failure to thrive (27 %). A total of 41 patients (73 %) developed clinically relevant post-procedural iatrogenic infection, resulting in a median of 3 (interquartile range [IQR] 2 – 4) endoscopic, radiological, and/or surgical interventions. Mortality rate was 2 %. Median total hospital stay was 12 days (IQR 6 – 17). Resolution of symptoms was reported in 40 of 46 patients (87 %) for whom long-term follow-up data were available (median follow-up 13 months, IQR 6 – 29). Conclusions ETD of symptomatic sterile WON resulted in high clinical success. Nonetheless, the majority of patients required additional reinterventions for clinically relevant post-procedural iatrogenic infection.