Peritoneal fibrosis formation is a consequence of inflammation/injury and a significant medical problem to be solved. The effects of soluble vascular endothelial growth factor (VEGF) receptor type I (sFlt-1) gene transfer on experimental peritoneal fibrosis were examined and compared to soluble transforming growth factor- (TGF-) receptor type II (sTGFRII) gene transfer. Male C57BL/6 mice were injected with 1.5 x 10⁸ plaque-forming unit (pfu) of adenovirus encoding active TGF- (AdTGF) intraperitoneally. Some mice had been treated with sTGFRII or sFlt-1 plasmid injection into skeletal muscle with electroporation 4 days prior to virus administration. Mice were euthanized at day 14 after virus administration. AdTGF induced significant elevation of serum active TGF-, caused significant inflammatory response [weight loss, elevation of serum amyloid-P (SAP) and IL-12, increased expression of monocyte chemoattractant protein-1 (MCP-1) mRNA], and induced marked thickening of the peritoneum and collagen deposition. Gene transfer of sFlt-1 reduced the collagen deposition approximately 81% in mesenteric tissue. Treatment with sFlt-1 decreased intercellular adhesion molecule-1 (ICAM-1) and MCP-1 mRNA expression significantly. Significant negative correlation between serum sFlt-1 and placental growth factor (PlGF) level was observed, whereas there was no significant negative correlation between sFlt-1 and VEGF. On the other hand, sTGFRII treatment enhanced the AdTGF-induced inflammation (significant elevation of SAP, TNF-, and IL-12 levels, and upregulation of ICAM-1 and MCP-1 mRNA expressions), and failed to prevent collagen deposition. These observations indicate that sFlt-1 gene transfer might be of therapeutic benefit in peritoneal fibrosis.