Absence of a functional p53 gene product can lead to increased p53 accumulation in cancer cells. In this contribution, the association between cell differentiation, chemotherapy and p53 immunoreactivity in human HT29 colon cancer cells grown in scid mice as undifferentiated cells and as mucin containing signet-ring cells was investigated. Mutated p53 was more frequently expressed in the undifferentiated tumour cells than in the signet-ring cells. 5-fluorouracil (5FU) treatment resulted in a substantial increase in the p53-positive signet-ring cell population (from 17% to 45%) and in an increased Mdm2 immunoreactivity. These findings indicate that mutated p53 expression is related to the differentiation pattern and that tumour cells devoid of mutated p53 immunoreactivity are preferentially eliminated by 5FU treatment.