OBJECTIVE To investigate the indications, resection rate, and safety of endoscopic submucosal dissection (ESD) for neoplastic lesions in the gastrointestinal tract at a European referral center. METHODS We carried out a retrospective analysis of the ESD procedures performed in our center for mucosal neoplastic and submucosal lesions of the gastrointestinal tract. The duration of the procedure, en bloc and complete (R0) resection rates, and complication rates were evaluated. Variables were reported as mean ± SD or simple proportions. Univariate analysis and comparisons of procedure times and resection rates were performed using Mann-Whitney U tests, or χ(2) tests for dichotomous variables. RESULTS Between 2007 and 2011, ESD was performed in a total of 103 patients (46.7% male, mean age 64.0 ± 12.7 years). The indications for the procedure were epithelial tumor (n = 54), submucosal tumor (n = 42), or other (n = 7). The total en bloc resection rate was 90.3% (93/103) and R0 resection rate 80.6% (83/103). The median speed of the procedure was 15.0 min/cm(2). The complete resection rate was lower for submucosal tumors arising from the muscle layer (68%, 15/22, P < 0.05). Resection speed was quicker for submucosal tumors localized in the submucosal layer than for lesions arising from the muscularis propria layer (8.1 min/cm(2) vs 17.9 min/cm(2), P < 0.05). The R0 resection rate and speed were better in the last 24 mo (90.1%, 49/54 and 15.3 min/cm(2)) compared to the first 3 years of treatment (73.5%, 36/49, P < 0.05 and 22.0 min/cm(2), P < 0.05). Complications occurred in 14.6% (n = 15) of patients, including perforation in 5.8% (n = 6), pneumoperitoneum in 3.9% (n = 4), delayed bleeding in 1.9% (n = 2), and other in 2.9% (n = 3). Only one patient with delayed perforation required surgical treatment. During the mean follow-up of 26 ± 15.3 mo, among patients with R0 resection, recurrence occurred in one patient (1.2%). CONCLUSIONS ESD is an effective and safe method for resection of neoplastic lesions with low recurrence. Speed and the R0 resection rate increased after 50 procedures.