In order to scrutinize the possible significance of (nonatypical) mucous cell hyperplasia of the pancreas to neoplasia, we analyzed these lesions in terms of c-Ki-ras activation, which is known to be very frequent in pancreatic carcinomas. A total of 16 such mucous cell hyperplasias were collected from 10 pancreases resected for chronic pancreatitis. Tiny tissue fragments were taken from hematoxylin-stained sections by microdissection, and DNA analysis was carried out by the polymerase chain reaction amplification and oligonucleotide hybridization methods. Activating mutations of c-Ki-ras oncogene at codon 12 were detected in 10 of the 16 lesions (62.5%), a high rate as seen in carcinomas. The results indicated a clonal origin of cells comprising the mucous cell hyperplasia suggesting a neoplastic and/or precancerous nature.