PURPOSE: To examine the impact of photodynamic therapy (PDT) on pigment epithelium derived factor (PEDF) expression in human choroidal neovascularization (CNV) membranes with regard to vascular endothelial growth factor (VEGF) expression. DESIGN: Interventional case series. METHODS: Retrospective review of interventional case series of 42 patients (42 eyes) who underwent removal of CNV. CNV was secondary to age-related macular degeneration (AMD) in all cases. Fifteen patients were treated with PDT, 3 to 246 days before surgery. CNV were stained for CD34, CD105, cytokeratin 18, VEGF, and PEDF. Twenty-seven CNV without previous treatment were used as control. RESULTS: Specimens without pretreatment disclosed varying degrees of vascularization, VEGF, and PEDF expression by different cells. Specimens treated by PDT, three days previously showed mostly occluded vessels lined with damaged endothelial cells (EC). In contrast, specimens excised at later time points after PDT were highly vascularized with healthy EC. This chronology was associated with an impressive VEGF immunoreactivity increased considerably in retinal pigment epithelial cells as well as significantly reduced PEDF expression in EC and stroma. CONCLUSIONS: PDT induces a selective vascular damage in CNV. The effectiveness of PDT, however, seems to be jeopardized by a rebound effect initiated by an enhanced VEGF and reduced PEDF expression in CNV.