Matrix metalloproteinase–2 (MMP2) is a key enzyme in the process of extracellular matrix remodeling involved in tumor invasion and metastasis. The activation of MMP2 involves interplay with the membrane type–matrix metalloproteinase–1 (MT1–MMP) and the tissue inhibitor of metalloproteinase–2 (TIMP2). In vitro, activated hepatic stellate cells are a main source of MMP2 and collagen I induces MMP2 activation. The steady–state mRNA levels of MMP2, MT1–MMP, TIMP2, collagen I, collagen IV, and laminin γ1 were compared with MMP2 activity in 55 hepatocellular carcinomas, 47 matching nontumor biopsies and 19 histologically normal livers. In hepatocellular carcinomas, increased collagen I mRNA levels were strongly associated with those of MMP2 (Spearman R = .74, P < .001), MT1–MMP (R = .65, P < .001) and TIMP2 (R = 0.61, P < .001). MMP2 activity was correlated with the mRNA expression of collagen I (R = .45 P < .01), collagen IV (R = .40, P < .01) and laminin γ1 (R = .33, P < .05). Unlike collagen IV and laminin γ1 mRNAs, MMP2, MT1–MMP, TIMP2, collagen I mRNA levels were increased in nonencapsulated compared with encapsulated tumors (P < .05). In addition, MMP2 activity was fourfold higher (P < .01) in tumors arising in cirrhotic livers than in those arising in noncirrhotic livers. Moreover, tumor recurrence was associated with 4.6– and 2.8–fold (P < .05) higher collagen I and MMP2 mRNA levels, respectively, in hepatocellular carcinomas arising in cirrhotic livers. Thus, a high extracellular matrix remodeling favors tumor progression in hepatocellular carcinomas.