In 1990, Longacre and Fenoglio-Preiser introduced "serrated adenoma (SA)" combining architectural and cytological features of hyperplastic polyp and adenomatous epithelium. It has been reported that intramucosal carcinoma occurs in 10% of SAs. Although there have been many reports on SAs, its histogenesis and natural history still remain unknown. To clarify the genetic changes in SA, APC mutations in 28 SAs, 4 adenocarcinomas in/with SAs, 12 tubular adenomas (TAs) and 10 adenocarcinomas in/with TAs were evaluated in the present study. After polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) analyses, gene mutations were confirmed by direct sequencing. No APC mutation was detected in adenocarcinomas in/with SAs, and only one SA without adenocarcinoma (3.8%) was found to be positive for APC gene mutation, whereas the mutations were found in 66.7% of TAs and in 50% of adenocarcinomas in/with TAs. The frequency of APC gene mutation in SAs was significantly lower than that in control sporadic TAs. These findings suggest that SAs are genetically different from TAs.