Objectives: the objective of this trial is to compare the effects of mesalazine and Nortriptyline on diarrhea predominant irritable bowel syndrome (IBS-D) patients for relief of abdominal pain, discomfort and abnormal bowel habits and stool frequency recorded daily. Design: a triple blind, randomized clinical trial. Setting and conduct: in this study, 40 patients with irritable bowels syndrome with diarrhea are randomly assigned to receive mesalazine or Nortriptyline. Before allocation, all patients were completed Beck questionnaire for screening of depression. Major Inclusion and Exclusion criteria: the main exclusion criteria were the use of analgesic drugs; pregnant women; breast feeding; patients with major depressive disorder (MDD) according to DSM-IV-TR; gastrointestinal bleeding; presence of any finding in favor of organic disorders in the lab tests; or organic disorder in colonoscopy of high risk patients, use of illicit drugs; patients with mixed and constipation predominant irritable bowel syndrome. Intervention: mesalazine (tablet 500 mg oral twice a day) as intervention and Nortriptyline (tablet 10 mg oral, once daily) for control group for 8 weeks. Main outcome measures variables: abdominal pain, the IBS, Symptom Severity Scoring measure (IBS,SSS), which contains five 100 point scales, that assess the severity of abdominal pain, the frequency of abdominal pain, dissatisfaction with bowel habits, and interference with quality of life, incomplete evacuation, stool frequency recorded daily and bloating are measured and compared between groups at the baseline and 8 weeks after the intervention. In this study, patients, investigator and data analyzer will be blinded and case assignments will done with the drug store as a randomization center.