Objective :Prospective evaluation of tumor regression during external irradiation for head and neck squamous cell carcinomas and its association with long-term local control. Methods and Materials : Two hundred twenty-eight patients with histologically confirmed squamous cell carcinoma [oral cavity: 59 (26%), oropharynx: 65 (29%), hypopharynx: 37 (16%), larynx: 67 (29%)] were included between January 1986 and December 1990. Curative intent external irradiation delivered 65–70 Gy over a period of 7 weeks (five 2 Gy fractions per week). Tumor regression was evaluation clinically and endoscopically every week. Results : Tumor regression, assessed at 2 weeks, was as follows: no response: 62 (30%), 25% response: 121 (59%); 50% response: 23 (11%). At 5 weeks, 9 (4%) patients showed 0–25% regression, 75 (33%) showed 50% regression, 115 (50%) showed 75% regression, and 29 (13%) showed complete regression. Median follow-up was 79 months (range: 6–96 months). The local control probability was 68% (62–74%) at a years, 65% (59–70%) at 5 years. Univariate analysis showed that, at 2 weeks, local control was significantly different between the nonresponders and the patients with 25% or greater response ( p < 0.025) and that, at the fifth week, local control was very different between the major responders (75 and 100%) and the minor responders (0–50%) ( p<0.0001). Multivariate analysis (Cox Proportional Hazards Model) showed that the probability of local relapse was significantly and independently increased for minor regression at 5 weeks [Relative risk (RR) of failure was 2.3 (1.4 – 3.7)], for nonlaryngeal tumors [RR: 2.4 (1.3 – 4.5)]. and for Stage T3–T4 [RR:2.4 (1.4 – 4)]. There prognostic groups can, therefore, be proposed: 1) low risk of recurrence when regression ⩾75% and laryngeal tumor or T1–T2 tumors in other sites: 106 (46.5%) patients, 2-year local control probability: 84% (77–92%); 2) high risk of recurrence: regression ⩽ 50% and T3–T4 nonlaryngeal tumors: 44 (19%) patients, 2-year local control probability: 27% (13–41%); 3) intermediate risk of recurrence: 78 (34.5%) patients, 2-year local control probability: 69% (58–80%). Conclusion : The present study suggests that tumor regression during externl radiotherapy is an independent predative factor of local control in head and neck carcinomas.