Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cirrhosis (PBC). The long-term administration of UDCA might indirectly favor colon carcinogenesis by increasing the fecal excretion of secondary bile acids or, in contrast, it might inhibit colon carcinogenesis, as demonstrated in animal models. In patients with PBC, we examined the effect of prolonged UDCA administration on the prevalence and recurrence of colorectal adenoma and on the proliferation of colon epithelial cells. One hundred fourteen patients (103 women, 11 men; mean age, 55 years) with PBC, were enrolled in a colonoscopic surveillance program. The prevalence of colon adenoma was compared in patients already treated with UDCA (mean duration 46 months) at the time of colonoscopy (treated group, n = 52) and in patients undergoing colonoscopy just prior to treatment initiation (untreated group, n = 62). The recurrence of adenoma following removal (mean follow-up, 35 months) was compared between UDCA-treated patients and appropriate age- and gender-matched controls (2/1) selected from a cohort of 205 patients undergoing polypectomy. Epithelial cell proliferation was assessed using anti-Ki67 antibodies on colon biopsies from both treated and untreated patients. Treated and untreated patients displayed similar demographic characteristics. The prevalence of colorectal adenomas was 13% in the treated group versus 24% in the untreated group (P = .16). The colon epithelial cell proliferation index was significantly lower in treated patients than in untreated patients (P = .001). Following removal of the adenoma, the probability of recurrence was significantly lower in patients treated with UDCA than in controls (7% vs. 28% at 3 years, P = .04). In conclusion, this study suggests that, in patients with PBC, the prolonged administration of UDCA (1) is not associated with an increased prevalence of colorectal adenomas, and (2) significantly decreases the probability of colorectal adenoma recurrence following removal. These results are strengthened by the significant reduction in colon epithelial cell proliferation seen in patients treated with UDCA.