Biopsies of the esophagus, stomach, and intestine are most often obtained using the traditional advance-and-close method with flexible endoscopes by extending an open forceps several millimeters beyond the endoscope tip to sample the mucosa, all under direct vision. We developed an alternative "turn-and-suction" endoscopic biopsy technique that permits the acquisition of larger mucosal samples. The biopsy forceps is advanced into the lumen, opened, and withdrawn backward until it is flush with the endoscope tip. Next, the endoscope tip is turned gently into the wall while air is suctioned from the lumen, and the biopsy forceps is very slightly advanced and then closed, usually without direct visualization. After straightening the endoscope tip, the biopsy is obtained by withdrawing the forceps and avulsing a superficial mucosal sample. By using this new method, we have safely taken over 10,000 biopsies without complications in endoscopic surveillance research protocols in patients at risk for gastrointestinal cancer. To compare the sizes of biopsies obtained with these two techniques, histologic sections of 341 mucosal samples from 12 patients with chronic ulcerative colitis were studied retrospectively. The mean greatest length of biopsy sections using the traditional technique was 4.72 mm, and using our new technique was 7.35 mm (56% longer). The turn-and-suction endoscopic biopsy method is best applied when flat mucosa is randomly sampled to seek microscopic pathologic changes that are not visible endoscopically, and may be advantageous for various non-histologic research analyses of gastrointestinal mucosa which are limited by tissue quantity.