We investigated the effect of hepatocyte growth factor (HGF) on collagen metabolism in cultured fibroblasts from scleroderma (SSc) patients and discussed the possible mechanism of its effect. Synthesis of matrix metalloproteinase-1 (MMP-1) and collagen and mRNA levels of various cytokines were examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. Hepatocyte growth factor enhanced MMP-1 production and mRNA levels of MMP-1 and Ets-1 (a transcriptional factor of MMPs). In addition, HGF suppressed collagen synthesis and mRNA levels of procollagenα1(I) and connective tissue growth factor (CTGF) in SSc fibroblasts. Expression of transforming growth factor (TGF)-β1 was not inhibited significantly in SSc or control fibroblasts. Hepatocyte growth factor also increased interferon (IFN)-γ mRNA significantly in SSc and control fibroblasts. Addition of anti-HGF antibody neutralized these effects of HGF on MMP-1 and collagen synthesis. The results suggest that HGF can suppress collagen accumulation in SSc fibroblasts by increasing MMP-1 levels possibly via activation of Ets-1 and also by decreasing collagen synthesis, which may be partly related to inhibition of CTGF, and increasing IFN-γ levels rather than the effect on TGF-β1. The present study indicates that HGF may be a promising therapeutic agent for this intractable disease.