Background & Aims: Patients with familial adenomatous polyposis (FAP) have a high prevalence of duodenal adenomas, and the region of the ampulla of rater is the predilection site for duodenal adenocarcinomas. This study assessed the risk of stage IV periampullary adenomas according to the Spigelman classification and periampullary adenocarcinomas in Swedish FAP patients screened by esophagogastroduodenoscopy (EGD). The genotype of patients with stage IV periampullary adenomas and periampullary adenocarcinomas was also investigated. Methods: A retrospective study of 180 patients screened by EGD in 1982-1999 was undertaken. Kaplan-Meier analysis was performed to evaluate cumulative risk. Mutation analysis was carried out in patients with periampullary adenocarcinomas diagnosed outside the screening program, in addition to patients in the screening group with stage IV periampullary adenomas and adenocarcinomas. Results: Periampullary adenoma stage IV was diagnosed in 14 patients (7.8%), with a cumulative risk of 20% at age 60 years. Periampullary adenocarcinoma was diagnosed in 5 patients (2.8%), with a cumulative risk of 10% at age 60. Three of the adenocarcinomas occurred in patients with stage IV periampullary adenomas compared with 2 in patients with less severe periampullary adenomatosis at screening (odds ratio, 31; 95% confidence interval, 4.6-215). Fifteen (88%) of the APC gene mutations were detected; 12 of these were located downstream from codon 1051 in exon 15. Conclusions: The life time risk of severe periampullary lesions in FAP patients is high, and an association between stage IV periampullary adenomas and a malignant course of the periampullary adenomatosis is strongly suggestive. Mutations downstream from codon 1051 seem to be associated with severe periampullary lesions.