Background: The concept of progressive fibrosing interstitial lung diseases (PF-ILD) has been recently proposed to describe a progressive phenotype in fibrosing ILDs, separate from the classical differential diagnosis of ILDs. However, we still do not know enough about how we can differentiate PF-ILD patients from non–PF-ILD patients in advance or how we can predict decline of lung function in PF-ILD patients. Periostin is a matricellular protein playing a critical role in the pathogenesis of pulmonary fibrosis significantly high in idiopathic pulmonary fibrosis patients. Methods: In this study, we applied three periostin ELISA systems—an original ELISA system recognizing total periostin, an ELISA system recognizing only the monomeric periostin, and a modified ELISA system that can measure periostin independently of the IgA complex established in this study—to serum from idiopathic interstitial pneumonia (IIP) patients to address whether periostin can differentiate PF-ILD from non–PF-ILD patients in advance, whether periostin can predict the decline of lung function in PF-ILD patients, and which ELISA system for periostin is the most suitable for these purposes.Results: We established the modified ELISA system using SS16A recognizing the R3 domain instead of SS18A recognizing the R1 domain as the primary mAb that can measure periostin independently of the IgA complex. All periostin values found by the three systems were significantly higher in PF-ILD patients than in healthy subjects in addition to SP-D and KL-6, whereas all the periostin values, but not SP-D or KL-6, could differentiate PF-ILD patients from patients with IIP other than PF-ILD, in the order of the monomer system, the modified system, and the original system. Moreover, the periostin values by all three systems, but not SP-D or KL-6, showed significant correlations with decline of either %VC or DL, CO, in order of the monomer system, the modified system, and the original system.Conclusions: Serum periostin, but not SP-D and KL-6, differentiates PF-ILD from non–PF-ILD and predicts decline of lung function in PF-ILD patients. The monomer periostin ELISA system is the best at doing so. These results demonstrate that periostin, particularly the monomeric form, is useful in treating PF-ILD patients.