Epidemiological, morphological, and molecular differences exist between carcinomas of the right and left sides of the large bowel. To investigate whether this is reflected in differences in somatic mutation frequency in the background mucosa, mutation of the neutral O-acetyltransferase gene (oat) was quantified in histologically normal resection margins from 20 informative (heterozygous) patients with caecal or ascending colon cancer (11 males, median age 75 years) and 20 with sigmoid colon or rectal cancer (10 males, median age 70 years). Mutant discordant crypts lacking O-acetyltransferase activity were visualized by mPAS staining and classified as wholly or partially involved by the mutant phenotype; median frequencies (x10(-4) were compared (Mann-Whitney U-test) after assessing a sample of more than 10,000 crypts per case. No significant difference was found between the frequencies of wholly involved mPAS-positive crypts in background mucosa of left- and right-sided cancers (p = 0.4569), indicating that tumours on both sides of the colon are associated with similar levels of lifetime-accumulated stem cell mutational load. However, partially involved mPAS-positive crypts were significantly more frequent in mucosa from left-sided cancers (p < 0.04), indicating increased mutational activity during the previous 12 months. Analysis of mucosa proximal and distal to left-sided cancers showed that this increase was due to a statistically higher frequency of partially involved crypts in proximal mucosa, which probably resulted from the obstructive effects of the tumour causing increased exposure of the proximal mucosa to luminal carcinogens and/or epithelial regeneration in response to low-grade inflammation or ischaemia. The findings indicate that although left-sided colonic cancer is commoner than right-sided cancer in the British population, carcinomas on both sides of the large bowel arise in a background of similar levels of stem cell mutational activity.