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To investigate the effectiveness and safety of mesalazine, with or without Lactobacillus casei, in preventing recurrence of symptomatic diverticular disease of the colon.Both mesalazine and probiotics showed recently their effectiveness in obtaining remission of symptomatic uncomplicated diverticular disease of the colon. Consistent data are not available on the optimal therapy to prevent recurrence of symptomatic diverticular disease of the colon.Multicenter, prospective, randomized, open-label study. Ninety consecutive patients (36 men, 54 women, mean age 67.5 y, range 39 to 84 y), previously affected by symptomatic uncomplicated diverticular disease of the colon (remission obtained with rifaximin 800 mg/d plus mesalazine 2.4 g/d for 10 d, followed by mesalazine 1.6 g/d for 8 wk), were enrolled in a 12-month follow-up. The following symptoms were assessed at entry and through follow-up by using a quantitative scale: (1) constipation, (2) diarrhea, (3) abdominal pain, (4) rectal bleeding, and (5) mucus with the stools. After recruitment, the patients were randomly assigned to one of the following 3 groups: mesalazine 1.6 g/d (group M), L. casei DG 16 billion/d for 15 d/mo (group L); mesalazine 1.6 g/d+L. casei DG 16 billion/d for 15 d/mo (group LM).Eighty-five patients completed the study (94.5%): 2 patients (2.22%, 1 of group M and 1 of group LM) were withdrawn from the study for protocol violation and 1 (1.11%) for hospital admission due to acute pulmonary disease (group L); 2 patients (2.22%) were lost to follow-up. Seventy-five patients (88.2%) were symptom free after the 12th month of treatment (overall symptomatic score: (0): 23/27 patients of group M [on intention to treat: 76.7% confidence interval (CI 95%: 61.5 to 91.8)], 23/29 of group L [on intention to treat: 76.7% (CI 95%: 61.5 to 91.8)], 29/29 of group LM [on intention to treat: 96% (CI 95%: 94.2 to 100)] (P<0.05). Only 10 patients (11.1%) showed recurrence of symptoms (overall symptomatic score: 68).Both mesalazine and L. casei DG seem to be effective in preventing recurrence of symptomatic uncomplicated diverticular disease of the colon, but their association seems to be more promising in this field.