Background: Double-balloon enteroscopy (DBE) is a new technique that allows high-resolution visualization, biopsies, and therapeutic interventions in all segments of the GI tract. The objective of the study was to evaluate the indications, the safety, and the clinical impact of DBE. Methods: This is a retrospective analysis conducted at 4 European medical centers. A total of 62 patients with suspected or documented small-bowel diseases were investigated by DBE. A total of 89 procedures were performed (26 and 9 patients from the oral or the anal route, respectively; 27 patients from both). The main outcome measurements were complications, depth and time of insertion, diagnostics, and therapeutics rates. Results: No complications occurred. Mean time was 70 ± 30 minutes and 90 ± 35 minutes from the oral and the anal route, respectively. Length of insertion was 254 ± 174 cm beyond the pylorus, 180 ± 150 cm beyond the ileocecal valve, whereas the entire small bowel was completely explored in 10 patients. DBE was diagnostic in 80% of the patients: in 29 of 33 of patients with GI bleeding, in one of 5 patients with iron deficiency anemia and positive fecal occult blood testing, in 3 of 5 patients with chronic diarrhea, in two of 3 patients with abdominal pain, in two of 3 patients with GI cancer (follow-up), in all patients with suspected or refractory celiac disease, and in two of 3 patients with Crohn’s disease. Treatment was performed in 41.9% of patients (22 polyps and 29 angioectesias). Conclusions: DBE is a safe and feasible diagnostic and therapeutic tool for suspected or documented small-bowel diseases. At present, the best candidates for the procedure appear to be those with obscure GI bleeding. Background: Double-balloon enteroscopy (DBE) is a new technique that allows high-resolution visualization, biopsies, and therapeutic interventions in all segments of the GI tract. The objective of the study was to evaluate the indications, the safety, and the clinical impact of DBE. Methods: This is a retrospective analysis conducted at 4 European medical centers. A total of 62 patients with suspected or documented small-bowel diseases were investigated by DBE. A total of 89 procedures were performed (26 and 9 patients from the oral or the anal route, respectively; 27 patients from both). The main outcome measurements were complications, depth and time of insertion, diagnostics, and therapeutics rates. Results: No complications occurred. Mean time was 70 ± 30 minutes and 90 ± 35 minutes from the oral and the anal route, respectively. Length of insertion was 254 ± 174 cm beyond the pylorus, 180 ± 150 cm beyond the ileocecal valve, while the entire small bowel was completely explor ed in 10 patients. DBE was diagnostic in 80% of the patients: in 29 of 33 of patients with GI bleeding, in one of 5 patients with iron deficiency anemia and positive fecal occult blood testing, in 3 of 5 patients with chronic diarrhea, in two of 3 patients with abdominal pain, in two of 3 patients with GI cancer (follow-up), in all patients with suspected or refractory celiac disease, and in two of 3 patients with Crohn’s disease. Treatment was performed in 41.9% of Patients (22 polyps and 29 angioectesias). Conclusions: DBE is a safe and feasible diagnostic and therapeutic tool for suspected or documented small-bowel diseases. At present, the best candidates for the procedure appear to be those with obscure GI bleeding.