Colonic carcinogenesis is accompanied by progressive genetic changes and alterations in growth control. To examine whether abnormalities of apoptosis are involved in carcinogenesis, we examined epithelial apoptosis in formalin-fixed normal and neoplastic colon by terminal uridine deoxynucleotide nick end-labeling (TUNEL) histochemistry. In normal colon, resection margins, and hyperplastic polyps, TUNEL-positive cells comprised around 3% of total colonocytes, with over 85% of these cells located in surface epithelium between crypts. In adenomas, there were significantly fewer TUNEL-positive cells at the luminal surface than normal (1.82 +/- 0.51% of epithelial cells, compared with 12.1 +/- 2.3%, P < 0.05) and a trend to increased numbers at the crypt base (2.70 +/- 0.98% compared with 0.65 +/- 0.15%). Carcinomas contained fewer TUNEL-positive cells than normal (1.7 +/- 0.27%), and they are randomly distributed. Transitional mucosa had significantly more TUNEL-positive colonocytes than normal (11.0 +/- 3.0%, P < 0.005), both at the surface and crypt base. These results show that colonocyte apoptosis normally occurs mainly in luminal cells but that early during carcinogenesis the distribution and quantity of apoptotic cells changes.