Microvascular surgery has emerged as an attractive area for recent advances in the field of gene therapy. The present study investigated the survival of ischemic, experimental skin flaps after treatment with the gene encoding vascular endothelial growth factor (VEGF). In 30 Sprague-Dawley rats, anterior abdominal skin flaps supplied by the epigastric artery and vein were created. Ten animals were treated with a mixture of liposomes and the cDNA encoding the 121-amino acid isoform of VEGF. Another 10 animals were treated with control plasmid DNA and liposome transfection medium; a third group of 10 animals was given physiologic saline. Each solution was injected directly into the femoral artery distal to the origin of the epigastric pedicle supplying the flap. Four days after injection, the pedicle was ligated and blood flow in the flap was approximated using dye fluorescence. Seven days later, the amount of viable tissue within the flap was measured by planimetry. After the animals were killed, specimens from both the operated and nonoperated sides of the abdomen were harvested for immunohistologic evidence of VEGF protein expression. Average dye fluorescence indices of the three groups (VEGF cDNA, control plasmid, and saline) 2 hours after pedicle ligation were 35.9, 23.9, and 53.9 percent, respectively (p < 0.05). Compared with the two control groups, flaps receiving VEGF cDNA had significantly greater tissue viability at the end of 7 days: 93.9 versus 28.1 percent for the control plasmid DNA group and 31.9 percent for the saline group (p < 0.05). Immunohistochemical staining documented increased deposition of VEGF protein in flaps that were infused with the VEGF cDNA versus saline alone (p < 0.05). The results indicated that the survival of ischemic tissues can be enhanced by administration of a cDNA encoding VEGF, a protein known to be important in the process of angiogenesis and wound healing.