Twenty-one consecutive patients with primarily non-resectable adenocarcinoma of the rectum were treated with preoperative split-course radiotherapy (40 Gy) and simultaneous sequential methotrexate + 5-fluorouracil + leucovorin (MFL). An initial infusion of methotrexate (250 mg/m2) was followed in the 2nd hour by 5-FU--first a bolus injection (10 mg/kg) and then continuous infusion (35 mg/kg/24 h) for 72 h. Leucovorin rescue (15 mg every 6 h) was initiated 24 h after the initial injection. Radiotherapy (10 Gy) was given with two 2.0 Gy fractions on days 1 and 2, and one fraction on day 3. The toxicity of the treatment was mostly mild to moderate. Compared with a previous consecutive series comprising 38 patients who received preoperative irradiation (greater than or equal to 40 Gy) only, with a resectability rate of 34%, the 71% resectability rate with this treatment seems to be superior.