The aim of this study was to evaluate when the serum level of KL-6, a sensitive marker for idiopathic pulmonary fibrosis (IPF), rise prior to clinical onset of IPF. Eight hepatitis C virus (HCV)-positive patients with IPF were enrolled in this trial. The serum samples of these eight patients were stored -80 degrees C every 1-3 month during a follow-up period and enzyme-linked immunosorbent assay (ELISA) for KL-6 was done at the same time. Diagnosis of IPF was based on computed tomography and/or histology. Diagnosis of clinical onset of IPF was based on presence of dyspnea, dry cough, and audible fine crackles. At 1 year before clinical onset of IPF, the sensitivities of serum marker for IPF were 75% (6/8) for KL-6, 25% (2/8) for each of lactic acid dehydrogenase (LDH) and C-reactive protein (CRP). At 2 years before clinical onset of IPF, the sensitivities of the same serum markers were 62.5% (5/8), 12.5% (1/8) and 0% (0/8), respectively. The sensitivity of KL-6 at 1 and 2 year before clinical onset of IPF was significantly higher compared with LDH and CRP. Our results indicate that many future patients with IPF may have high levels of serum KL-6 at 1 or 2 years before clinical onset of IPF, suggesting that changes in serum KL-6 level can provide useful information for the early diagnosis of IPF in patients with HCV.