Both docetaxel and irinotecan have shown strong radiosensitizing properties in vitro. Encouraging results have been reported by phase I/II studies on combined docetaxel or irinotecan with radiotherapy. In the present study we investigated the feasibility of double radiosensitization with weekly docetaxel and irinotecan in head and neck cancer. Twelve patients with locally advanced squamous cell head and neck cancer were recruited in a phase I/II dose escalation protocol. Radiotherapy was given as a standard fractionation regimen (2 Gy/day, 5 fractions/week) to a total dose of 66-70 Gy. Three Docetaxel/Irinotecan dose levels were examined thus, 20/25 mg/m2 (level 1), 20/40 mg/m2 (level 2) and, 25/55 mg/m2 (level 3). Severe asthenia was observed in 1/4 patients treated in the 2nd dose level and in all 4 patients treated in the 3rd. The onset of severe asthenia was associated with the onset of severe grade 3/4 mucositis during the 4th week of treatment. Radiation induced mucositis was accompanied by fungal infection in all 5 patients. The symptomatology persisted for 10-14 days. Mild grade 2 mucositis was observed in 7/8 patients treated at the 1st and 2nd dose level, which enforced treatment delay for 3-5 days. Neutrophil toxicity was minimal. There was only one patient treated at the 3rd dose level that presented with grade 2 neutropenia. Hemoglobin toxicity was also minimal, showing a median drop of 1.2 gr/dL. There was no platelet toxicity observed. Complete response was observed in 9/12 (75%) patients and partial response was observed in 3/12 patients. Of interest, the lowest CR rate was observed in the 3rd dose level (2/4; 50%), which may be a consequence of overall treatment time prolongation. It is concluded that docetaxel and irinotecan combination with radiotherapy is feasible and, a high CR rate can be expected. Combination of the regimen with cytoprotective agents warrant further investigation.