The antigen KL-6, a mucin-like high-molecular-weight glycoprotein, is expressed on type-2 pneumocytes and bronchiolar epithelial cells. Serum levels of KL-6 have been shown to correlate well with the activities of several different kinds of interstitial pneumonia. The purpose of this study was to assess the usefulness of monitoring serum KL-6 levels in patients who had received thoracic radiotherapy (TRT). In particular, the usefulness of such a protocol for the early diagnosis of severe radiation pneumonitis (RP) and the evaluation of its progress and severity was examined. Serum KL-6 levels were retrospectively monitored in 16 patients with lung cancer who had received TRT with or without chemotherapy. Eight of these patients had developed severe RP and eight had developed localized (within the irradiated field) RP. Serum KL-6 levels were measured using a modified sandwich-type enzyme-linked immunosorbent assay. In patients who developed severe RP, serum KL-6 levels showed a consistent tendency to increase after the clinical diagnosis of RP. In four patients, serum KL-6 levels even began to rise before a clinical diagnosis of severe RP had been made. In the patients with localized RP, on the other hand, the serum levels did not show any tendency to increase during or after TRT. Moreover, patients whose serum KL-6 levels rose more than 1.5 times higher than their pre-treatment serum KL-6 level, had a large chance of developing severe RP that was unresponsive to steroid hormones and resulted in death. Serum KL-6 levels, therefore, should be useful indicators for the early diagnosis of severe RP and for estimating its progress and severity in patients treated with TRT.