Mice were given up to 9 doses of methotrexate intermittently over a 3-week period. Inhibition of mitosis occurred in the duodenum, jejunum and ileum after the first injection, and after 2 doses the crypt epithelium showed megalocytosis and occasional abnormal mitotic figures. Further treatment produced degeneration of the epithelium of the villi, which became irregular and atrophic, and the amount of crypt tissue was greatly reduced. Focal ulceration and haemorrhage occurred in some animals. Changes in the caecum and colon developed later and were much milder. After withdrawal of methotrexate the intestinal mucosa rapidly recovered and was normal 1 week later.