The causes of irritable bowel syndrome (IBS) remain obscure. Some investigators have proposed chronic low-grade mucosal inflammation as a potential etiological factor. We performed a systematic review to examine this issue in detail. MEDLINE, EMBASE, and EMBASE classic were searched up to December 2010 to identify studies of case-control design applying tests for low-grade inflammation to either full-thickness intestinal or endoscopic mucosal biopsies from patients with IBS. Controls were required to be healthy individuals, or asymptomatic patients undergoing investigation for reasons other than the reporting of upper or lower gastrointestinal symptoms. Individual study results were summarized descriptively. The literature search identified 1388 citations, of which 16 studies were eligible for inclusion. Individual study results were diverse, partly as a consequence of the different surrogate markers for inflammatory mechanisms studied. Mast cells, T lymphocytes, B lymphocytes, and mucosal cytokine production all appeared altered among cases with IBS in individual studies, while no study demonstrated a significant difference in numbers of plasma cells, neutrophils, or eosinophils. Some studies suggested a relationship between mast cell abnormalities and symptom severity and frequency, as well as co-existent fatigue and depression. Studies were limited by the lack of comparability of controls, and the fact that most were conducted in highly selected groups of patients with IBS. Low-grade mucosal inflammation, particularly mast cell activation, may be a contributory factor in the pathogenesis of IBS. Mast cell stabilizers warrant further assessment as a potential therapy in the condition.