OBJECTIVES: Techniques of tissue sampling at endoscopic retrograde cholangiopancreatography (ERCP) have been underutilized due to technical demands, low yield, and lack of immediate intraprocedural diagnosis. The objective of this study was to describe a new inexpensive, highly efficient ERCP tissue processing, and interpretation technique to address these issues. METHODS: A retrospective, institutional review board approved, single-center study was done at a tertiary-care medical center. Between June 2004 and February 2009, 133 patients (age 38-95 years; men 53%) with suspicious biliary strictures underwent ERCP with tissue sampling using a new technique. Small forceps biopsy specimens were forcefully smashed between two dry glass slides, immediately fixed, stained with rapid Papanicolaou, and interpreted by an on-site pathologist during the procedure (Smash protocol). RESULTS: Of the 117 proven to have cancer, true-positive Smash preps included pancreatic cancer 49/66 (74%), cholangiocarcinoma 23/29 (79%), metastatic cancer 8/15 (53%), and other 4/7 (57%). The median number of Smash biopsies to diagnosis was 3 (range 1-17). Suspicious or atypical results were considered to be negative in this study. There were no false positives and no complications. Smash had an overall sensitivity of 89/117 (76%) for all cases. The true-positive yield of immediate Smash prep cytology, combined with ERCP fine needle aspirate (FNA) and forceps biopsy histology was 77/95 (81%) for primary pancreaticobiliary cancers. CONCLUSIONS: Immediate cytopathologic diagnosis at ERCP was established in 72% of patients presenting with suspected malignant biliary obstruction using a new cytological preparation of forceps biopsies. This approach to ERCP tissue sampling permits immediate diagnosis and avoids the need for subsequent procedures, adds little cost and time, and is safe to perform.