Purpose: Accelerated repopulation in head-and-neck carcinomas might be related to the expression of proliferative factors such as epidermal growth factor receptor (EGFr). The present study focuses on the prognostic value of EGFr for T-site control and the relation to tumor cell differentiation and overall treatment time. Methods and Materials: We studied 336 patients treated with primary radiotherapy using 66-68 Gy, 2 Gy per fraction and overall treatment times of 9 1/2, 6 1/2, or 5 1/2 weeks. Pretreatment biopsies were stained for EGFr. Results: Thirty-five percent of the carcinomas had less than 50% of the area stained for EGFr. Small T-size and well-differentiated tumors was associated with a high degree of staining (p = 0.001 and p = 0.002, respectively). EGFr was of poor prognostic influence regarding local control in patients treated with 9 1/2 weeks split-course, whereas the opposite was found for patients given accelerated treatment in 5 1/2 weeks. A similar relationship between outcome, overall treatment time, and differentiation has previously been shown. The two parameters were analyzed together by separating the tumors with low EGFr and/or poor differentiation from tumors with well/moderate differentiation and high EGFr, resulting in odds ratios for T-site failure of 12 (1.43-104), 0.91 (0.51-1.65), and 0.43 (0.17-1.08), for treatment times of 9 1/2, 6 1/2, and 5 1/2 weeks, respectively. Conclusion: The tumor response to variations in fractionation is heterogeneous, and the prognostic impact of EGFr and-differentiation might be relative and dependent on the overall treatment time of radiotherapy. (C) 2004 Elsevier Inc.