KL-6, surfactant protein (SP)-A, SP-D, and monocyte chemoattractant protein-1 (MCP-1) are reported to be sensitive markers for interstitial lung diseases (ILD). However, each marker has been studied independently. The aim of this study was a comparative analysis of the diagnostic values of these markers. Subjects consisted of 33 patients with ILD (21 cases of idiopathic pulmonary fibrosis and 12 associated with collagen vascular diseases) and 82 control subjects (12 cases of bacterial pneumonia and 70 healthy volunteers). Receiver operating characteristic curves revealed that KL-6 was superior to the other markers. The cut-off levels for these markers that resulted in the highest diagnostic accuracy were determined to be 465 U/ml for KL-6, 48.2 ng/ml for SP-A, 116 ng/ml for SP-D, and 1080 pg/ml for MCP-1. The sensitivity, specificity, and diagnostic accuracy were 93.9%, 96.3%, and 95.7% for KL-6; 81.8%, 86.6%, and 85.2% for SP-A; 69.7%, 95.1%, and 87.8% for SP-D; and 51.5%, 92.7%, and 80.9% for MCP-1; respectively. The serum levels of SP-A and SP-D, but not of KL-6, were significantly higher in patients with bacterial pneumonia than in healthy volunteers. These results suggest that of the markers studied, KL-6 is the best serum marker for ILD.