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. We studied 336 patients treated with primary radiotherapy using 66-68 Gy, 2 Gy per fraction and overall treatment times of 912, 612, or 512 weeks. Pretreatment biopsies were stained for EGFr.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 weeks split-course, whereas the opposite was found for patients given accelerated treatment in 5 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 912, 612, and 512 weeks, respectively. 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.