We investigated the effect of granulocyte colony-stimulating factor (G-CSF) administration on radiotherapy (RT)-induced oral mucositis in 26 consecutive patients with head and neck neoplasms, stages III and IV, treated with hyperfractionated RT. The first 13 patients were treated with RT alone and the remainder with RT + G-CSF. The two groups of patients were similar in age, sex, PS, primary site, stage, RT schedule and RT volume. Daily mucositis, median mucositis score, day of highest mucositis, requirement of parenteral nutrition, weight loss, treatment break, number of days of RT interruption were analyzed during RT treatment. No statistically significant differences were found between the two groups except for the number of patients who interrupted the treatment: 9/13 patients (69%) in the RT alone group versus 3/13 (23%) in the RT + G-CSF group (p < 0.05). Our observations indicate that G-CSF did not appear to have influenced the objective mucositis although it reduced the number of treatment breaks. In consideration of the cost of G-CSF, its prophylactic administration should be reserved only for patients at high risk of RT interruption.