Until recently, only the proximal small bowel was accessible for diagnostic and therapeutic endoscopy. This paper describes experience in the first 275 patients examined and treated with the new method of double-balloon enteroscopy (DBE), which is expected to make full-length enteroscopy possible. Between November 2003 and May 2005, double-balloon enteroscopy was conducted in 275 consecutive patients presenting at two tertiary referral hospitals. The characteristics of the patients, indications for the procedures, procedural parameters, and diagnostic yield are described here. All conventional treatment options were available. The tolerability of the procedure was assessed in a small subset of the patients. After the procedure, the patients were monitored in a recovery room for at least 2h. They were discharged afterwards, provided there were no signs of complications or complaints. The main indication for DBE was suspected small-bowel bleeding (n=168), and the lesions responsible for the bleeding were found in 123 patients (73 %) and treated in 61 (55 %). In patients with refractory celiac disease (n=25), DBE revealed a high proportion (six patients, 23 %) of enteropathy-associated T-cell lymphomas that had not been suspected on other tests. Further DBE indications were surveillance and treatment of hereditary polyposis syndromes (n=20); and suspected Crohn's disease, which was diagnosed with DBE in four of 13 patients (30 %). No relevant pathology was found in 24 % of the patients. Panenteroscopy was successfully performed in 26 of 62 patients (42 %) in whom it was attempted, in either one or two sessions. The average duration of the procedures was 90 min (range 30 - 180 min, SD 42), and the average insertion length was 270 cm (range 60 - 600 cm, SD 104). Patients' tolerance of the procedure was excellent. Severe complications were recognized in three cases (1 %), all involving pancreatitis. This large pilot series shows that DBE is a well-tolerated and safe new endoscopic technique with a high diagnostic yield in selected patients.