The effects of recombinant gamma-interferon (rec gamma-IFN) on collagen production by confluent monolayer cultures of progressive systemic sclerosis (PSS) dermal fibroblasts were studied. Five cell lines obtained from patients with rapidly progressive disease of recent onset were examined. All PSS fibroblast cell lines exhibited increased collagen production when compared with normal skin cell lines. It was found that rec gamma-IFN caused potent inhibition of PSS fibroblast collagen production in a concentration-dependent manner. Greater than 50% inhibition was observed with as little as 50 antiviral units/ml, and maximal effects were attained at a concentration of 500 units/ml. The rec gamma-IFN caused reproducible inhibition of collagen production by the 5 PSS fibroblast cell lines, ranging from 58.9% to 85.6% of control values. Measurement of type I and type III procollagen messenger RNA (mRNA) levels with specific complementary DNA probes demonstrated a coordinate reduction of greater than 60% in mRNA for both transcripts in rec gamma-IFN-treated cells, compared with control cells. These findings indicate that rec gamma-IFN can modulate the excessive collagen biosynthesis characteristic of PSS fibroblasts and that this effect can be explained largely by the gamma-IFN-mediated decrease in specific collagen mRNAs.