Besides a genetic predisposition, a causal role of various environmental factors has been considered in the etiology of ulcerative colitis (UC). The association between appendectomy and UC has recently been the subject of intense scrutiny in the hope that it may lead to the identification of important pathogenetic mechanisms. Published data from animal models of colitis demonstrated reduction in experimental colitis after appendectomy, especially if performed at an early age. Several epidemiological case control and cohort studies have shown a strong and consistent relationship. The metaanalysis of 17 case-controlled studies showed an overall odds ratio 0.312 (95% confidence intervals = 0.261-0.373) in favor of appendectomy (p < 0.0001). One of the two recent large cohort studies is in agreement with these results, but the other failed to confirm them. All these studies have suggested that alterations in mucosal immune responses leading to appendicitis or resulting from appendectomy may negatively affect the pathogenetic mechanisms of UC. Further investigation of the role of appendectomy in UC is expected to open new fields for basic scientific research and may lead to the improvement of our understanding for the disease pathogenesis.