Aims and Background When combined with radiotherapy, fluoropyrimidines have been shown to have synergistic effects on various tumor types. Doxifluridine (5-dFUR) is a 5-fluorouracil (5-FU) prodrug that is transformed into 5-FU in neoplastic tissue, which suggests that it may improve the activity of radiotherapy. The aims of this study were to evaluate the feasibility and efficacy of the combination of radiotherapy and oral 5-dFUR plus I-leucovorin in terms of pathologically complete remissions in locally advanced rectal cancer. Methods Eleven patients with locally recurrent (n = 7) or primary unresectable rectal cancer (n = 4) were treated with three cycles of oral I-leucovorin 25 mg/dose followed by 5-dFUR 750 mg/m² twice daily for four days every 12, in combination with pelvic radiation at a standard dose of 45 Gy over five weeks. The tumor burden was assessed by means of CT and endoscopic ultrasound at baseline and at least four weeks after the end of the treatment and before surgery. Results Four patients achieved an objective response, 6 disease stabilization and 1 had progressive disease. After a median time of five weeks from the end of treatment 8 patients underwent radical resection and a pathologically complete remission was documented in 2. Seven of these patients are still alive and disease free after a median follow-up of 18 months. The major side effects were grade 3 diarrhea in one case, and grade 1-2 nausea and vomiting in three cases. No significant hematological toxicity was observed. Conclusions This combination of radiation and 5-dFUR plus I-leucovorin led to an interesting rate of resectability, with pathological downstaging being documented in two cases. These preliminary results show an encouraging local control of an otherwise unresectable disease. Combined preoperative therapy with oral fluoropyrimidine plus I-leucovorin together with radiation may be an attractive approach in patients with operable rectal cancer.