This study used a prospectively managed clinical database in order to identify 1470 patients with gastrointestinal cancers receiving protracted venous infusion (PVI) fluorouracil (5FU). It aimed to determine the time course of toxicity due to PVI 5FU and to analyse factors predicting toxicity. The initial development of stomatitis occurred more rapidly than diarrhoea or palmar plantar erythema (PPE). The percentage of patients with National Cancer Institute Common Toxicity Criteria (CTC) grade 2 or worse PPE peaked at 9% between weeks 8 and 17, whereas this peak occurred earlier for stomatitis and diarrhoea. The development of CTC grade 1 toxicity in the first 28 days after commencement of chemotherapy was classified as early grade 1 toxicity. Multivariate Cox regression analysis showed that female sex, better performance status, elevated bilirubin, early grade 1 PPE and early grade 1 diarrhoea were independent prognostic factors for the development of CTC grade 2 or worse PPE (P<0.01). Female sex, increased age, elevated alanine transaminase and urea and early grade 1 PPE were significant independent prognostic factors for the development of CTC grade 2 or worse stomatitis (P<0.01). Early CTC grade 1 diarrhoea predicted CTC grade 2 or worse diarrhoea (P<0.01). Older, female patients with good performance status and impaired liver and renal function who develop early grade 1 PPE alone or in combination with diarrhoea are at highest risk of subsequently developing grade 2 or worse PPE or stomatitis during treatment with PVI 5FU. Reduction of infused 5FU dose should be considered for these patients. Such an approach could both reduce severe toxicity owing to chemotherapy and minimise treatment delays, and should be evaluated prospectively.