Encouraging results have recently been reported in patients (pts) with locally advanced unresectable squamous cell carcinoma of the head and neck (SCCHN) when induction chemotherapy (IC) is used and followed by radiotherapy (RT). The present study assessed the therapeutic response of an aggressive regimen consisting of docetaxel (TXT), cisplatin (CDDP) and 5-fluorouracil (5-Fu) as IC and concurrent with RT in pts with locally advanced (stages III and IV) SCCHN. 42 pts (35 male and 7 female) with a mean age of 58 years suffering from stages III and IV (Mo) SCCHN were included to this organ preservation phase II clinical trial. The site of the primary tumors was the anterior mouth in 9 pts, base of tongue and oropharynx in 12, middle third of the face in 8 and larynx in 13. The performance status of the pts was 0-1 according to WHO and above 80% according to Karnofsky classification. IC consisted of TXT (40 mg/m2), CDDP (40 mg/m2) and 5-Fu (350 mg/m2) every two weeks (wks) for a total of four courses and repeated, coupled with RT (66-68 cGys total dose fractionated at 200 Gy per day, 5 days a week), for up to seven wks. In total, pts received eight courses of chemotherapy (CT) at the end of RT treatment. Pts were evaluated at the end of IC, after RT and every six wks thereafter. 41 pts were eligible for evaluation after IC (one died from myocardial infarction) and 39 after completion of treatment (two died during RT). Statistical multivariate analysis was performed using SPSS (11) package. Complications from IC and RT were evaluated according to WHO criteria and included mucositis Grade (Gr) IV in 10% of the pts, Gr III in 50%, Gr II in 20%. Anemia presented in 40% of the pts with Gr II, 40% with Gr I, neutropenia 17% with Gr IV, 20% with Gr III, 30% with Gr II, thrombocytopenia 3% with Gr III, 10% with Gr I and xerostomia up to Gr II in 70% of the pts. The response rate (RR) after IC was complete response (CR) for 10 pts (24.4%), partial response (PR) for 22 (53.7%) and no response (NR) for 9 (21.9%). At the end of the treatment the RR in the intention-to-treat population were CR for 25 pts (64.1%), and PR for 14 (35.9%). Follow up ranges from 18 to 56 months (mts). 14 pts died during follow-up time. The mean survival time is 41 mts and the median 40. 2 pts with CR developed local recurrence and two distant metastases, whereas all pts with PR developed progressive disease (PD) and all but two are dead from disease. It is evident from this phase II study that TXT-CDDP-5Fu based IC followed by the same regimen coupled with RT improves local control. Pts that showed CR after IC continued to maintain disease status during RT (P-value=0.0181). In pts with SD concurrent RT did not alter dramatically disease outcome. Patients who showed complete response after both IC and RT presented a four-year survival rate of 74% compared to a 30% to partial responders (P-value=0.0001). Results are encouraging and further study of the toxicity and follow-up is needed to validate treatment effectiveness.