The sequential histochemical changes during colon carcinogenesis were studied in male Sprague-Dawley rats given 16 weekly subcutaneous injections of 15 mg 1,2-dimethylhydrazine per kg body wt and serially killed at regular intervals. Cryostat sections were used to study the mucus content of the colonic mucosa with the periodic acid Schiff's reaction, and enzyme histochemical methods were applied to investigate the activity of some key enzymes of carbohydrate metabolism at different stages of carcinogenesis. Enlarged mucus-rich crypts with a marked hypercellularity (149% of control as determined morphometrically) appearing very early during carcinogenic treatment revealed almost normal activities of glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Hyperbasophilic crypts lacking mucus production were observed later and showed a loss of G6Pase, but marked increase of G6PDH and GAPDH activity. Mucus-rich signet ring cell carcinomas showed the same enzymatic pattern as the mucus-rich crypts, whereas mucus-free adenocarcinomas and undifferentiated carcinomas revealed a loss of G6Pase and highly increased G6PDH and GAPDH activities. The results showed that focal changes in polysaccharide content and in the activity of some enzymes of carbohydrate metabolism, as observed in various organs, also accompany the carcinogenic process in the colon. This supports the concept that aberrations in carbohydrate metabolism play an important role during the process of carcinogenesis.