Background: Procurement of cytologic samples by brushing is common practice at endoscopic retrograde cholangiopancreatography (ERCP) but has low sensitivity for cancer detection. Limited data are available on other techniques, including endoluminal fine-needle aspiration and forceps biopsy. This series reviews the yield of these three stricture sampling methods. Methods: In this prospective study, patients with biliary obstruction with a clinical suspicion of malignancy underwent triple-tissue sampling at one ERCP session. Final cancer diagnosis was based on all sampling methods plus surgery, autopsy, and clinical follow-up. Tissue specimens were reported as normal, atypia, or malignant. Results: A total of 133 patients were evaluated: 104 had cancer and 29 had benign strictures. Tissue sampling sensitivity varied according to the type of cancer; the highest yield was seen in ampullary cancers (62% to 85%). The cumulative sensitivity of triple-tissue sampling in the cancer patients was as follows: sensitivity was 52% if atypia was considered benign and 77% if it was considered malignant. The addition of a second or third technique increased sensitivity rates in most instances. No serious complications occurred from the tissue sampling methods. Conclusions: Tissue sampling sensitivity varied according to the type of cancer. Combining a second or third method increased sensitivity; general use of at least two sampling methods is therefore recommended. (Gastrointest Endosc 2000;51:383-90.)