Purpose: To define the effect of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis. Materials and methods: Mouse tongue mucosal ulceration was analysed as the clinically relevant endpoint. Graded single or fractionated dose irradiation (10 × 3 Gy/2 weeks, graded test doses on day 14) were combined with topical administration of dexpanthenol or a base, with or without Aloe vera extract. The formulations were applied for 14 days (single dose) or 24 days after the first fraction. Results: Single dose irradiation resulted in an ED₅₀ (dose at which a positive mucosal response was expected in 50% of the animals irradiated) of 11.9 ± 1.2 Gy. None of the formulations yielded a significant change in incidence or time course of ulceration. Test irradiation after 10 × 3 Gy gave an ED ₅₀ of 9.0 ± 0.1 Gy. Base treatment increased the ED ₅₀-values to 10.5 ± 0.8 Gy (p = 0.0095) and 9.9 ± 0.7 Gy (p = 0.0445) without or with Aloe vera. Dexpanthenol resulted in ED ₅₀ values of 9.5 ± 0.1 Gy without Aloe vera (p > 0.05), and of 10.9 ± 0.9 Gy (p = 0.0035) with Aloe vera. The latent time to ulceration was prolonged, compared to the control (6.3 days) without Aloe vera (8.0-8.2 days, p < 0.001) and with dexpanthenol and Aloe vera (7.3 days, p = 0.0239). Conclusions: With single dose irradiation, neither dexpanthenol nor Aloe vera extract significantly changed the oral mucosal radiation response. With fractionated irradiation, drug administration significantly increased the isoeffective radiation doses, independent of dexpanthenol or Aloe vera content. Neither dexpanthenol nor Aloe vera display a prophylactic potential.