OBJECTIVES: Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal hamartomas. The hamartomas are located predominantly in the small intestine and may cause intussusceptions. We aimed to assess the characteristics, risk, and onset of intussusception in a large cohort of PJS patients to determine whether enteroscopy with polypectomy should be incorporated into surveillance recommendations. METHODS: All PJS patients from two academic hospitals were included in this cohort study (prospective follow-up between 1995 and July 2009). We obtained clinical data by interview and chart review. Deceased family members with PJS were included retrospectively. Cumulative intussusception risks were calculated by Kaplan-Meier analysis. RESULTS: We included 110 PJS patients (46% males) from 50 families. In all, 76 patients (69%) experienced at least one intussusception (range 1-6), at a median age of 16 (3-50) years at first occurrence. The intussusception risk was 50% at the age of 20 years (95% confidence interval 17-23 years) and the risk was independent of sex, family history, and mutation status. The intussusceptions occurred in the small intestine in 95% of events, and 80% of all intussusceptions (n = 128) presented as an acute abdomen. Therapy was surgical in 92.5% of events. Based on 37 histology reports, the intussusceptions were caused by polyps with a median size of 35 mm (range 15-60 mm). CONCLUSIONS: PJS patients carry a high cumulative intussusception risk at young age. Intussusceptions are generally caused by polyps > 15 mm and treatment is mostly surgical. These results support the approach of enteroscopic surveillance, with removal of small-intestinal polyps > 10-15 mm to prevent intussusceptions. The effect of such an approach on the incidence of intussusception remains to be established in prospective trials.