Background and Study Aims Esophagogastroduodenoscopy (EGD) can be routinely performed via a nasal route in adults by using small-caliber endoscopes. The aim of this study was to evaluate the adequacy of biopsy specimens obtained with small forceps for histologic diagnosis. Patients and Methods From January to April 2007, we prospectively compared all biopsy specimens obtained, during conventional EGD (8.8-mm-diameter endoscope), with (CS-EGD) or without sedation (C-EGD), and transnasal or transoral-EGD (4.9-mm-diameter endoscope) without sedation (T-EGD). All biopsy specimens were blindly evaluated by a pathologist. For each specimen, were recorded: site, biopsy size and thickness, type of lesion (focal or diffuse), and in case of focal abnormalities described by the endoscopist, presence of the histologic lesions in the targeted biopsies. Results One thousand and thirty-five biopsy specimens were obtained from 300 procedures (109 T-EGD, 48 C-EGD, and 143 CS-EGD): 983 biopsy specimens were untargeted (esophagus and cardia in 21%, stomach in 85% and duodenum in 84%) and 352 biopsy specimens were targeted to focal lesions (esophagus and cardia in 79%, stomach in 15%, and duodenum in 16%). The mean size of specimens was 1.8, 2, 2.2 mm diameter, in T-EGD, C-EGD, and CS-EGD groups, respectively (P<0.001). The whole thickness of mucosa was present in 68%, 84%, 71% of the cases among T-EGD, C-EGD, and CS-EGD groups, respectively (P=0.9). There was no significant difference in the rate of definitive histologic diagnosis from targeted or nontargeted biopsies according to the endoscopic procedure. Conclusions Biopsy specimens obtained during EGD with small forceps are as effective for diagnosis as those obtained with standard forceps.