It has been reported that radiotherapy-induced craniofacial deformities can occur in 66 to 100 percent of survivors of childhood head and neck cancers. Recent interest in the effectiveness of radioprotectors in the protection of normal tissue against radiation injury led us to investigate a possible role of radioprotection in the prevention of radiation-induced craniofacial bone growth inhibition. Therefore, the objective of this study was to use the radioprotective agent amifostine (Ethyol, WR-2721) as a probe to determine the effectiveness of radioprotection in the prevention of radiation-induced craniofacial bone growth inhibition after single-dose orthovoltage radiation to the infant rabbit orbital-zygomatic complex. Seven-week-old male New Zealand white rabbits were randomized into three groups (n = 10 each): group 1, 0 Gy (sham radiation); group 2, 35-Gy single-dose orthovoltage radiation; and group 3, 35-Gy single-dose orthovoltage radiation and amifostine (300 mg/kg intravenously, given 20 minutes before radiation). Serial radiographs and computed tomographic scans were obtained for cephalometric analysis, bone volume, and bone density measurements until skeletal maturity at 21 weeks. Significant (p < 0.05) reductions in orbital-zygomatic complex linear bone growth, bone volume, and bone density were observed after 35-Gy radiation compared with nonirradiated controls. No significant differences were noted between groups in cephalometric analysis of the nontreated (nonirradiated) left orbital-zygomatic complex, indicating no crossover effect from the radiation beam. However, pretreatment with amifostine, 20 minutes before 35-Gy radiation, resulted in significant (p < 0.05) preservation of linear bone growth, bone volume, and bone mineral density in the rabbit orbital-zygomatic complex compared with controls. This study demonstrated for the first time the effectiveness of a radioprotector in the prevention of radiation-induced craniofacial bone growth inhibition, and it paves the way for investigation into the pathogenic mechanism and prevention of radiotherapy-induced craniofacial deformities.