Cuffitis, considered a form of reminiscent ulcerative colitis (UC), is one of the common complications of ileal pouch-anal anastomosis (IPAA) and its disease course has not been systematically characterized. The aim was to examine the disease course of cuffitis in a large historical cohort. All patients with cuffitis diagnosed based on a combined evaluation of symptom and pouch endoscopy at the initial visit to our Pouchitis Clinic were included. Pouch patients with diagnoses other than cuffitis served as controls. Patients with familial adenomatous polyposis were excluded. A total of 120 patients with cuffitis were included. The control group consisted of 811 patients (normal pouch, n = 85; irritable pouch syndrome, n = 155; acute pouchitis, n = 170; chronic pouchitis, n = 128; Crohn's disease [CD] of the pouch, n = 185; and surgical complications, n = 88). After a median follow-up of 6 years (interquartile range: 3-10 years) after pouch construction, there were 40 (33.3%) having 5-aminosalicylate (5-ASA)/steroid-responsive cuffitis; 22 (18.3%) having 5-ASA/steroid-dependent cuffitis, and 58 (48.4%) developing 5-ASA/steroid-refractory cuffitis. Further investigation of the 58 patients with refractory cuffitis showed that 19 (32.8%) had CD of the pouch and 14 (24.1%) had surgical complications including fistulae and anastomotic sinuses. There were 16 (13.3%) cuffitis patients who developed pouch failure during the follow-up period. Cuffitis may represent a spectrum of diseases. In patients with refractory cuffitis, a diagnosis of CD or surgery-associated anal transitional zone complications should be considered.