Bifunctional PEG (polyethylene glycol) molecules provide a novel approach to retargeting viral vectors without the need to genetically modify the vector. In a previous report we showed that modification of the viral capsid by the addition of a peptide with binding preference for differentiated ciliated airway epithelia allowed gene delivery to those cells by a novel entry pathway. Here we demonstrate further the versatility of this method by coupling a protein, FGF2, to the surface of an adenovirus (Ad). This modification results in the elimination of the endogenous tropism of the virus and confers upon the virus a novel route of entry. Adenoviral vectors modified by the addition of FGF2 show enhanced efficiency of transduction of the ovarian cancer cell line SKOV3.ip1. This enhancement in transduction is dependent on the binding of the coupled FGF2 to its high-affinity receptor and is independent of coxsackie and adenovirus viral receptors. In an intraperitoneal model of ovarian cancer, Ad/PEG/FGF2 generates increased transgene expression in tumor tissue compared to unmodified Ad. Furthermore, polymer modification of adenovirus vectors results in reduced localization of adenovirus to nontarget tissues and a marked decrease in Th1 and Th2 T cell responses. In conclusion, the approach described here may lead to the development of a gene therapy vector capable of targeting a therapeutic gene to diseased cells, while minimizing toxicity and expression in other tissues.