It has been reported that serum levels of KL-6 and surfactant protein D(SP-D) can be useful indicators for interstitial pneumonia(IP). In the present study, we evaluated the clinical significance of KL-6 and SP-D by measuring the serum levels of patients with various pulmonary diseases by enzyme-linked immunosorbent assay. Serum levels of KL-6 in patients with idiopathic interstitial pneumonia(IIP), collagen disease with interstitial pneumonia(CDIP), lung cancer(LC) and LC with idiopathic interstitial pneumonia were significantly higher than of those in healthy controls. Moreover, serum levels of KL-6 were significantly higher in patients with active IP than in those with inactive IP. Serum levels of SP-D in patients with IIP and CDIP were significantly higher than of those in healthy controls. When a cut-off level of KL-6 or SP-D in sera was defined as a value of healthy controls representing the means + 2SD, the serum KL-6 positive diagnostic rate for IP(79.2%) was higher than that of SP-D(66.7%). The SP-D positive diagnostic rate for lung diseases other than IP(11.6%) was lower than that of KL-6(34.9%). The serum concentration of KL-6 in patients with the pulmonary diseases significantly correlated with that of SP-D. These findings suggest that KL-6 may be superior in the sensitivity of IP and can be used to evaluate the disease activity of IP. In addition, SP-D may be more specific for IP than KL-6.