Biomodulated 5-flourouracil (5-FU) chemotherapy may limit disease progression in up to 50% of patients with metastatic or unresectable carcinoma of the colorectum. However, treatment is expensive and may be toxic. Thus any predictors of response may be clinically and economically valuable. The p53 gene is mutated in more than 50% of colorectal tumours, usually resulting in p53 overexpression. It may regulate cell cycle progression and cellular response to DNA damage. The principal anticancer activity of 5-FU is due to its ability to induce DNA damage. Fifty-nine patients received bolus intravenous 5-FU/folinic acid over 3 months. Response was assessed by CAT scan (WHO criteria). p53 protein overexpression was determined immunohistochemically from paraffin sections of the original primary tumour and resected metastases. Tumour over expression of p53 protein was associated with a lower rate of response and a higher rate of deterioration both radiologically (P < 0.03) and clinically (P < 0.05, chi 2 test for trend), but did not predict survival from start of treatment. Response was unrelated to age, sex, tumour grade, site of disease or chemotherapy schedule. Tumour p53 protein overexpression alone cannot be used to select advanced colorectal cancer patients for chemotherapy but may be useful in association with other markers of tumour biology.