Purpose: To determine whether hepatocyte growth factor (HGF) and connective tissue growth factor (CTGF) are involved in the development of proliferative vitreoretinopathy (PVR) and a new model of PVR pathogenesis. Methods Immunohistochemical methods were used to demonstrate the presence of HGF and CTGF in cryostat sections of human PVR membranes using specific antibodies; RPE cell proliferation, migration and attachment simulated by HGF and CTGF were analyzed by 3H-uptake, Boyan chamber and modified MTT assay, respectively. The effect of HGF on RPE cell junction was evaluated by electronic microscope and cofocol microscopy .the effect of TGFβ on CTGF upregulation was assessed by western Blot, HGF and CTGF induced RPE cell proliferation and the development of experimental PVR were conducted by injection of adenovirus-HGF and CTGF vectors into rabbit subretina. The concentrations of HGF and CTGF in PVR were determined using ELISA. Results In each of the human PVR membranes, stromal cells were immunohistochemically positive for both HGF and CTGF. HGF induced significant RPE junction disruption in organ culture; overexpression of HGF inducing the formation of multilayered groups of migratory RPE cells by adenovirus HGF injection. The concentration of HGF in vitreous of adenovirus HGF injected rabbits was much higher than that of control. CTGF induced RPE proliferation, migration and attachment in a dose dependent manner for the range 10ng/ml to 100 ng/ml. CTGF protein production was increased by the treatment of TGFβ maximally at 30ng/ml. A strong fibrotic membrane was formed in rabbit epiretina by vitreous injection of adenovirus CTGF vector. The highest concentration of CTGF in vitreous was found in PVR patients by ELISA assays. Conclusions HGF and CTGF are expressed in human PVR membranes. The proliferation, migration and attachment of RPE were stimulated by both CTGF and HGF; HGF is the major factor in disassembling the junction of RPE cell and initiating the migration of RPE in the early stage of PVR development. At a later stage of PVR under the influence of CTGF, RPE cells become myofibroblastic and fibrosis occurs and retinal traction is induced. The delineation of the roles of HGF and CTGF in the pathogenesis of PVR will provide a therapeutic target for the treatment strategies of PVR.