Post-infective irritable bowel syndrome (PI-IBS) is characterized by continuing symptoms of irritable bowel syndrome, typically diarrhea-predominant, following an episode of acute gastroenteritis. There is often an increase in sub-epithelial inflammatory and neuroendocrine cells on colonic mucosal biopsy. Mesalamine is an anti-inflammatory agent, effective in the treatment of inflammatory bowel disease. The goal of this study was to compare mesalamine to placebo on symptoms and quality-of-life (QOL) in PI-IBS. Twenty patients who developed diarrhea-predominant IBS after gastroenteritis were randomized to receive mesalamine (Asacol®) 1.6 gm b.i.d. or placebo for 12 weeks in a double-blind placebo-controlled study. QOL was assessed using the IBS-QOL questionnaire. Stool frequency, stool consistency, urgency, severity of abdominal pain, severity of bloating, and global-improvement scale were recorded in daily diaries for 7 days at baseline and every 4 weeks. Data were analyzed by comparing the change from baseline to last follow-up. One patient withdrew after randomization; data were incomplete in two patients. Thus, data were analyzed from 17 patients (11 men and 6 women, median age: 27 years, range 22–45 years). Mesalamine was not associated with significant improvement in global symptoms, abdominal pain, bloating, stool urgency, frequency, or consistency (all p ≥ 0.11) or QOL (p ≥ 0.16). There was no significant improvement in global symptoms or overall QOL with mesalamine in patients with PI-IBS.