A total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is considered the surgery of choice for definitive management of familial adenomatous polyposis (FAP) and some patients with ulcerative colitis (UC). However, this surgical treatment is often associated with pouchitis, a long-term complication that occurs mostly in UC patients. The purpose of this study was to better define the molecular background of pouchitis. A microarray-based survey was performed using pouch mucosal samples collected from 28 and 8 patients undergoing surgery for UC and FAP, respectively. There were 4,770 genes that significantly differentiated uninflamed from inflamed mucosal samples, and their functional features were represented mostly by metabolic and cell proliferation pathways. In contrast, functional analyses of aberrantly expressed genes between UC and FAP samples, irrespective of mucosal inflammation status, revealed multiple pathways and terms that were linked to changes in immune response. Interestingly, the comparison of uninflamed UC and FAP samples identified a set of 29 altered probe sets, including an inflammation-related transcript encoding a Charcot-Leyden crystal (CLC) protein. The most distinct changes in gene expression profiles differentiating uninflamed UC and FAP pouch mucosal samples were attributed to the Gene Ontology category innate immune response. Our study confirmed that alterations in immune responses can be found between patients who underwent surgery for UC and FAP, independent of the pouch inflammation status. This observation may be important when managing IPAA patients.