Patients with villous atrophy due to coeliac disease have an increased risk of developing small intestinal malignancies. Intestinal glutathione (GSH) and glutathione S-transferases (GST) are involved in the protection against carcinogenesis. The aim of this study was to evaluate GSH content and GST enzyme activity in small intestinal mucosa of untreated coeliacs compared to controls. We evaluated GSH content and GST enzyme activity, including the levels of GST classes alpha, mu, pi and theta, in small intestinal biopsies of untreated coeliacs (flat mucosa, Marsh IIIC, n = 12) compared to normal subjects (n = 23). Next, we evaluated GSH and GST's in coeliacs in remission (Marsh 0 - I, n = 11), coeliacs with persisting villous atrophy while on a gluten-free diet (partial villous atrophy, Marsh IIIA (n = 5); subtotal villous atrophy, Marsh IIIB (n = 6)) and patients with infiltrative / crypt-hyperplastic Marsh II lesions (n = 4). Total GST enzyme activity and content of GSTalpha are markedly suppressed in Marsh IIIC lesions compared to controls (resp. 220 +/- 79 vs. 464 +/- 189 nmol / mg protein*min (P < 0.001) and 2.79 +/- 2.46 vs. 6.47 +/- 2.29 mg / mg protein (P < 0.001)). In coeliacs in remission these levels normalized. Total GST enzyme activity and GSTalpha levels are proportionately lowered according to the degree of mucosal pathology in Marsh II, IIIA and IIIB. (Spearman's sigma correlation coefficient for total GST, -0.596, P < 0.001; GSTalpha, -0.620, P < 0.001). GSTmu, pi and theta and GSH levels are not significantly different in the selected study groups of mucosal pathology compared to controls. Total GST enzyme activity and content of GSTalpha in small intestinal mucosa are significantly lower in untreated coeliac disease compared to controls. In Marsh II, IIIA and IIIB, GST enzyme activity and GSTalpha content are proportionally lower according to the degree of mucosal pathology. Normal values are seen in coeliacs in remission. This correlation between coeliac disease and a suppressed GSH / GST detoxification system may explain in part the carcinogenic risk in untreated coeliac disease.