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Glutathione S-transferase (GST) enzymes catalyse the detoxification of by-products of reactive oxygen species and are thus important in cellular defence mechanisms. The GSTs are polymorphic with allelic variants encoding isoforms with functional differences. GST polymorphism has been associated with susceptibility and clinical outcome in patients with cancer. In this retrospective cohort, we have investigated associations between common GSTM1, GSTM3 and GSTP1 polymorphisms with factors known to influence clinical outcome and patient survival in colorectal cancer. Significant linkage disequilibrium was demonstrated between GSTM1 and GSTM3 alleles (P≤0.001). We identified no significant associations between the GSTP1Ile105Val105 polymorphism and any clinical outcome parameters or patient survival. However significant associations were demonstrated with mu class GSTs. Those patients who were GSTM1 null presented less frequently with poorly-differentiated tumours (P=0.038). Furthermore, patients who were GSTM3 AA were less likely to present with advanced stage tumours (T-stage, P=0.036 and Dukes' classifications, P=0.012) or distant metastases (P=0.017) when examined alone. Upon further examination of the effect of linkage disequilibrium, we found that, in GSTM1 null individuals, GSTM3 AA (compared with other GSTM3 genotypes combined) had longer disease-free survival (HR=0.54, 95% CI 0.30-0.98, P=0.044). Thus, the GSTM3 AA genotype is associated with improved prognosis especially in those with GSTM1 null. Our findings suggest that the GST mu gene cluster mediates tumour characteristics and survival in patients with colorectal cancer. Introduction Colorectal cancer is the third most common cancer worldwide and the World Health Organisation estimates that 945,000 new cases and 492,000 deaths occur yearly (1). The aetiology of colorectal cancer is believed to have both familial and environmental factors. It is estimated that familial colorectal cancer syndromes account for 5-15% of cancers (2), with the remainder of colorectal cancers comprising sporadic colorectal carcinoma, where interaction between genetic and environmental factors is proposed. Environmental factors including the contribution of diet-derived carcinogens (e.g. polycyclic aromatic hydrocarbons; PAH) have been proposed in some (3) but not all studies (4). Indeed, heterocyclic aromatic amines (HAAs) formed during cooking of meats have been shown to be colonic carcinogens in experimental animals (5). As glutathione S-transferase (GST) enzymes are involved in PAH metabolism, genetically-determined interindividual differences in the host's ability to detoxify such carcinogens may be important and thus mediate susceptibility to malignancies associated with environmental PAH exposure