Interferon-gamma (IFN-gamma) regulates the expression of collagen and fibronectin genes by molecular mechanisms not completely understood. We investigated the effects of IFN-gamma on the expression of the genes encoding alpha 1 (I) procollagen (COL1A1), alpha 1 (III) procollagen (COL3A1), and fibronectin (FN) in cultured normal human lung fibroblasts. Labeled newly synthesized proteins were analysed by electrophoresis, mRNA levels and stability by Northern hybridizations, and transcription rates by in vitro assays. IFN-gamma caused a reduction in the production of alpha 1 (I) and alpha 1 (III) procollagens and of fibronectin. The reduction in the production of procollagen chains was shown to result from a combination of IFN-gamma-induced inhibition of the transcription rates of the COL1A1 and COL3A1 genes and destabilization of the corresponding transcripts. IFN-gamma increased the transcription rate of FN, but also decreased the stability of the corresponding transcripts. The net results indicate that the regulation of the expression of extracellular matrix genes by IFN-gamma is a complex process that involves changes in gene transcription rates, alterations in mRNAs stability, and possibly, modulation of the rates of translation.