The aim was to quantify the effect of selective inhibition of the epidermal growth factor receptor (EGFR) on the radiation response of mouse oral mucosa to daily fractionated irradiation. Irradiation comprised graded single doses of 25 kV X-rays to the lower tongue surface or fractionated doses of 5 × 3 Gy week^-1 (200 kV X-rays) over 1 or 2 weeks, followed by graded local doses, to generate full dose-effect curves. For selective inhibition of EGFR, BIBX1382BS, a tyrosine kinase inhibitor, was administered orally at a dose of 50 mg kg^-1, for the entire overall treatment time. The ED₅₀ (the dose expected to induce ulcer in 50% of the mice) for untreated mucosa was 11.9 ± 1.2 Gy. Fractionated irradiation administered over 1 or 2 weeks yielded ED₅₀ values for the concluding test irradiation of 6.7 ± 2.1 and 6.5 ± 1.9 Gy, respectively. Administration of BIBX1382BS resulted in a non-significant increase of the top-up ED₅₀ to 8.3 ± 1.6 Gy (p = 0.1197) after 1 week and to 7.6 ± 1.6 Gy (p = 0.2263) after 2 weeks. EGFR inhibition does not alter the radiation response of oral mucosa to fractionated irradiation or interfere with mucosal repopulation processes. This indicates that the regulation of mucosal repopulation is largely independent of EGFR activation.