Abstract Objective Oral mucositis is a severe, dose-limiting side effect of radio(chemo)therapy for head and neck tumors. The epithelial radiation response (ulceration) is accompanied by inflammatory changes. Their interaction with the epithelial processes remains unclear. The present study was initiated to determine the effect of inhibition of TNF-α or COX-2 on the epithelial radiation response in the mouse tongue model. Methods Daily fractionated irradiation was given with 5 × 3 Gy/week over one (days 0–4) or two weeks (days 0–4, 7–11). Each protocol was terminated by graded test doses (5 dose groups, 10 animals each) to a defined area of the lower tongue surface to generate full dose–effect curves for mucosal ulceration. A TNF-α inhibiting antibody (Infliximab) or a COX-2 inhibitor (Celecoxib) was administered. Results No effect of Infliximab or Celecoxib was found in any of the protocols. Isoeffective doses for ulcer induction were unchanged. Also, the time course of the response was largely unaffected. Conclusions Inhibition of TNF-α or COX-2, two dominating inflammatory pathways, did not result in modulation of the response of oral epithelium during fractionated irradiation. This suggests that the inflammatory changes mediated through TNF-α or COX-2 are not relevant for the epithelial radiation response of oral mucosa.