Background: Targeted therapy, using biomarkers to assess disease activity in ulcerative colitis (UC), has been proposed. Objective: The objective of this study was to evaluate whether pharmacological intervention guided by fecal calprotectin (FC) prolongs remission in patients with UC. Methods: A total of 91 adults with UC in remission were randomized to an intervention group or a control group. Analysis of FC was performed monthly, during 18 months. A FC value of 300 mg/g was set as the cut-off for intervention, which was a dose escalation of the oral 5-aminosalicylate (5-ASA) agent. The primary study end-point was the number of patients to have relapsed by month 18. Results: There were relapses in 18 (35.3%) and 20 (50.0%) patients in the intervention and the control groups, respectively (p ¼ 0.23); and 28 (54.9%) patients in the intervention group and 28 (70.0%) patients in the control group had a FC > 300 mg/g, of which 8 (28.6%) and 16 (57.1%) relapsed, respectively (p < 0.05). Conclusion: Active intervention significantly reduced relapse rates, although no significant difference was reached between the groups overall. Thus, FC-levels might be used to identify patients with UC at risk for a flare, and a dose escalation of their 5-ASA agent is a therapeutic option for these patients.