Background and purpose: Oral mucositis is a frequent early side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is accompanied by inflammatory reactions; their interaction with epithelial processes remains unclear. The aim of the present study was to investigate the effect of pentoxifylline (PTX) on the oral mucosal radiation response in the mouse tongue model. Materials and methods: Irradiation comprised fractionation (5 fractions of 3 Gy/week) over 1 (days 0–4) or 2 weeks (days 0–4, 7–11), followed by graded local top-up doses (day 7/14), in order to generate complete dose–effect curves. PTX (15 mg/kg subcutaneously) was applied once daily over varying time intervals. Ulceration of mouse tongue epithelium, corresponding to confluent mucositis, was analyzed as the clinically relevant endpoint. Results: With fractionated irradiation over 1 week, PTX administration significantly reduced the incidence of mucosal reactions when initiated before (day − 5) the onset of fractionation; a trend was observed for start of PTX treatment on day 0. Similarly, PTX treatment combined with 2 weeks of fractionation had a significant effect on ulcer incidence in all but one experiment. This clearly illustrates the potential of PTX to ameliorate oral mucositis during daily fractionated irradiation. Conclusion: PTX resulted in a significant reduction of oral mucositis during fractionated irradiation, which may be attributed to stimulation of mucosal repopulation processes. The biological basis of this effect, however, needs to be clarified in further, detailed mechanistic studies.