Peritoneal fibrosis formation is a consequence of inflammation/injury and a significant medical problem to be solved. The effects of soluble VEGF receptor type I (sFlt-1) gene transfer on experimental peritoneal fibrosis were examined and compared with soluble transforming growth factor-β (TGF-β) receptor type II (sTGFβRII) gene transfer. Male C57BL/6 mice were injected with 1.5 × 108 plaque-forming unit of adenovirus encoding active TGF-β (AdTGFβ) intraperitoneally. Some mice had been treated with sTGFβRII or sFlt-1 plasmid injection into skeletal muscle with electroporation 4 days before virus administration. Mice were euthanized at day 14 after virus administration. AdTGFβ induced significant elevation of serum active TGF-β, 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 ∼81% in mesenteric tissue. Treatment with sFlt-1 decreased ICAM-1 and MCP-1 mRNA expression significantly. Significant negative correlation between serum sFlt-1 and placental growth factor level was observed, whereas there was no significant negative correlation between sFlt-1 and VEGF. On the other hand, sTGFβRII treatment enhanced the AdTGFβ-induced inflammation (significant elevation of SAP, TNF-α, 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.