To determine the usefulness of serum KL-6 levels for predicting the occurrence of radiation pneumonitis (RP) after the application of single high-dose stereotactic radiation therapy for lung tumors, the serum KL-6 levels were measured in 16 patients before irradiation and every 1 or 2 months thereafter. Three of the 16 patients experienced RP of grade 3 severity according to the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group toxicity criteria. RP occurred 3 months after the completion of radiation therapy in two patients, and 4 months after completion in one patient. RP occurred at significantly increased frequencies in patients with primary lung cancer (p = 0.01) and adenocarcinoma (p = 0.01), and in those undergoing the concurrent irinotecan therapy (p = 0.02). In all 16 patients, the lactate dehydrogenase level remained normal during the follow-up period. In all three of the patients with RP, KL-6 levels increased by > 1.5-fold compared to the pretreatment value and over the cutoff level of 500 IU. The ratio of the increase in serum KL-6 values 2 months after the patient had undergone irradiation showed a significant correlation with the occurrence of RP (p = 0.04). In conclusion, KL-6 is a useful marker for prediction of the occurrence of RP after single, fractional, high-dose stereotactic irradiation of lung tumors.