In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n ¼ 12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m À2 to 60 mg m À2 to 70 mg m À2 to identify the maximum tolerated dose (60 mg m À2 ). In phase II, 31 patients with nonresectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m À2 per day) for 5 weeks. Irinotecan (60 mg m À2 ) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity.