Abstract We evaluated the usefulness of serum levels of KL-6 and surfactant protein D (SP-D) as markers of interstitial pneumonia (IP) associated with collagen diseases in 115 patients. KL-6 and SP-D levels in patients with IP (n = 38) were significantly higher than those in patients without IP (n = 77). Moreover, KL-6 and SP-D levels in patients with active IP (n = 8) were significantly higher than those in patients with inactive IP (n = 30). Both KL-6 and SP-D proved useful for the diagnosis of IP associated with collagen diseases and for the evaluation of disease activity. We classified IP into three groups according to the extent of the lesion on computed tomographs of the chest. There was a significant difference among three groups in serum levels of KL-6, but not in serum levels of SP-D. KL-6 proved to be useful as an indicator of the extent of the IP lesions. We monitored changes in KL-6 and SP-D levels in seven of eight patients with active IP. Chronological changes of serum KL-6 and SP-D in patients with active IP were different. In fatal cases in particular, serum levels of SP-D decreased at the terminal stage of IP while levels of KL-6 continued to increase.