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Background: Serum markers, such as Krebs von den Lungen (KL-6), are reported to reflect the severity, progressiion and prognosis of idiopathic pulmonary fibrosis (IPF).We aimed to evaluate the usefulness of tumor markers to determine if they may be diagnostic markers for the connective tissue diseases (CTDs) predicting CTD-related interstitial lung diseases (ILDs) (CTD-ILD) development and to examine if there was a difference between ILD patients with CTD and without CTD (non-CTD-ILD).Methods: In our study, 146 patients with ILD only, 61with CTD-ILD, 102 with lung cancer (LC), 111 with chronic obstructive pulmonary disease (COPD), and 46 with CTD were included.Serum levels of several tumor markers were measured.Results: Compared with COPD, the levels of CEA, NSE, CYFRA21-1, CA19-9 and CA125 were higher (P<0.01 or P<0.05) but the level of SCC was lower (P<0.01)in ILD patients and there is significant difference in NSE, SCC, CYFRA21-1 and CA125 (P<0.01 or P<0.05) between CTD-ILD and non-CTD-ILD groups.Conclusions: It appears that tumor markers, NSE, SCC, CYFRA21-1 and CA19-9, may be predictive factors for CTD-ILD that could be used to identify the clinical development of CTD among ILD before it is detected on autoimmune symptoms or auto antibodies.However, future studies are needed to validate our findings and define whether levels of serum tumor markers have prognostic value or are applied to predicting progressive CTD-ILD.