Over-the-scope-clips (OTSC(®)) have been shown to be an effective and safe endoscopic treatment option for the closure of gastrointestinal perforations, leakages and fistulae. Indications for endoscopic OTSC(®) treatment have grown in number and also include gastro cutaneous fistula (GCF) after percutaneous endoscopic gastrostomy (PEG) tube removal. Non-healing GCF is a rare complication after removal of PEG tubes and may especially develop in immunosuppressed patients with multiple comorbidities. There is growing evidence in the literature that OTSC(®) closure of GCF after PEG tube removal is emerging as an effective, simple and safe endoscopic treatment option. However current evidence is limited to the geriatric population and short standing GCF, while information on closure of long standing GCF after PEG tube removal in a younger population with significant comorbidities is lacking. In this retrospective single-center case-series we report on five patients undergoing OTSC(®) closure of chronic GCF after PEG tube removal. Four out of five patients were afflicted with long lasting, symptomatic fistulae. All five patients suffered from chronic disease associated with a catabolic metabolism (cystic fibrosis, chemotherapy for neoplasia, liver cirrhosis). The mean patient age was 43 years. The mean dwell time of PEG tubes in all five patients was 808 d. PEG tube dwell time was shortest in patient 5 (21 d). The mean duration from PEG tube removal to fistula closure in patients 1-4 was 360 d (range 144-850 d). The intervention was well tolerated by all patients and no adverse events occured. Successful immediate and long-term fistula closure was accomplished in all five patients. This single center case series is the first to show successful endoscopic OTSC(®) closure of long lasting GCF in five consecutive middle-aged patients with significant comorbidities. Endoscopic closure of chronic persistent GCF after PEG tube removal using an OTSC(®) was achieved in all patients with no immediate or long-term complications. OTSC(®) is a promising endoscopic treatment option for this condition with a potentially high immediate and long term success rate in patients with multiple comorbidities.