SUMMARY. Background : Interferon gamma-1b (IFN-γ-1b), an antifibrotic agent, has been proposed as a novel therapeutic agent for idiopathic pulmonary fibrosis (IPF). The long-term clinical and molecular effects of this agent are still unknown. Experience with three IPF patients treated with IFN-γ-1b for 4-7 consecutive years is reported. Objectives : Three patients with histologically proven IPF were studied prospectively. They received IFN-γ-1b 200μg subcutaneously three times weekly, along with low-dose prednisolone. The patients were monitored for at least four years according the ATS/ERS criteria and the appearance of the lesions on high resolution computed tomography (HRCT). Methods : Using RT-PCR assay, the transcription levels of transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), and interferon–γ (IFN-γ) genes in lung tissue were evaluated before, and after two years of treatment. Results : Treatment was well tolerated and no acute exacerbation of the disease was observed in any patient. Pulmonary fibrosis remained stable in terms of symptoms and pulmonary function tests (PFTs), and improvement in HRCT scoring was detected in two of the three patients. Marked mRNA expression of TGF-β1 and CTGF, but complete lack of IFN-γ was detected in fibrotic lung tissue at baseline. After two years of treatment, all three patients exhibited increased expression of the IFN-γ gene (p<0.05), while TGF-β1 and CTGF transcriptional levels had not changed. Conclusions : Longterm treatment with IFN-γ-1b in patients with mild-to-moderate IPF appears to be safe. In two of the three patients monitored, the disease was stabilized, probably by enhancement of the expression of the IFN-γ endogenous gene. Πνεύμων 2009, 22(2):162-168.